Esper Genesis is the most "Mass Effect" sort of 5E sci-fi RPG. It is explicitly flavored to ultra-tech sci-fi and goes straight 5E on rules implementation. They have a meta-plot and a collection of 10 short adventures, but the game seems sadly unsupported by third parties these days, and I can't get my hands on the Master Technicians manual in hardcover (PDF only).
The starship combat is decent; it works along 5E lines, with the ship having an AC, hit points, and a structure value determining critical hits. There is a sort of 'ancient powers' theme running through the rules, and this even extends to the mechanic class having a "magic hologram bracelet" and "being able to fix and hack through projected energy."
I got it out to see if I wanted to keep or sell, and this one feels like a keep to me. But a sort of 'keep' where I wonder if I will play it that much. My most significant problem is the lack of adventures; even if I burn through the 10 released ones, I am on my own past that. This is a keeper of all of the 5E sci-fi games, but it has its own universe and "thing" going on.
If you don't want to stray too far from 5E but want a Mass Effect-style game and universe, this is an excellent place to land. Adventures will need to be your own, for the most part.
White Star is sort of the White Box equivalent of Esper Genesis, and it shares the same resolution mechanics for starship combat; ships have an AC and hit points, roll attacks with a d20, and you are done.
The framework for this game is more straightforward than EG; it borrows heavily from White Box, and if you want fantasy monsters and magic, crack open a White Box OSR game, and you are done. This includes Guardians of the Galaxy-type galactic hijinks to harder sci-fi like Traveller. The game has an "alt" Star Frontiers feel, too, a 'what if' game where Star Frontiers stuck with B/X and White Box-style rules instead of doing a percentile system.
The adventures are good here, too, and I have plenty to last. One problem with many sci-fi RPGs is that you randomly chart once the adventures run out, which gets dry. This has a lot of adventures, and you can even translate them into many OSR-style adventures if they are generic enough.
I love the dicing in this game, just a d20 and a few d6. White Box games remove the need for other dice and significantly streamline play, gear choice, and overall design. This is where to go if you want White Box B/X style sci-fi. This is one I will be playing soon.
Ultramodern 5 is also a keeper. This game is just so darn strange. I wish the organization was better; the game could be improved by half the word count and some very tough editing. The information on new skills and feats jammed in at the end of a life path chapter. There is too much equipment and far too many oddball sci-fi weapons and armor choices. I would have stuck to the basic options (lasers, projectiles, etc.) and presented the ultra-tech and odd weapons in a special section.
The team knows what it is doing regarding hacking and rebuilding the 5E character system. They do amazingly innovative things with birth, lifepath, ladder, class, and archetype. Archetypes replace subclasses, making them universal to all classes, such as brawler, diplomat, or driver. So if your class is a martial artist, you can pick the archetype of a gun dancer and have a fantastic combination of abilities. Ladders replace the ability score and feat progression track of classes and are themed around choices such as juggernaut, performer, or survivor.
As a mechanical hack of the 5E progression system, this game is full of unique ideas. I would love to see a fantasy game from this team.
The default campaign world feels like a Moebius-inspired Heavy Metal comic.
Overall, I like White Star the best since it feels like "d20 in space." This is a generic sci-fi game that could cover everything from Firefly, Star Wars, Battlestar Galactica, Star Trek, Alien, space truckers, and any other idea you throw at it in a d20 mush - just like D&D is a blend of many fantasy inspirations and sources into its own thing. Every system works like every other system; understand d20 personal combat, and you understand mech, vehicle, and starship combat.
Esper Genesis wins on presenting a strongly themed "Mass Effect" style setting with an ancient mystery and many star-faring races trying to work together or compete to understand and harness its power. Everything from creatures, powers, weapons, gear, and tech is consistent and well-presented. The game is beautiful and laid out very well.
Ultramodern 5 is a hacker's resource for sci-fi 5E gaming. I wish this game was better laid out, and it didn't seem like ideas running into each other. The way they rebuild the 5E progression system is fantastic and surpasses even Level Up A5E's work in the area.
And then, of course, is one of the best d20 sci-fi games, Cypher System, and its sister game, Numenera. I keep coming back to Cypher for sci-fi just because the sci-fi genre is supposed to be so full of the unknown, and the 5E model, where you must have stats, gear listings, and monster entries for everything, ruins the wonder and mystery of the game.
I could easily invent a laser-resistant jelly slime with acid skin in the Cipher System. Level 4 creature, 12 hits, hindrance of 2 levels versus energy weapons, and gives an ongoing damage condition of 2 points of damage per round until a successful Might defense roll (level 4) is made. Make the creature vulnerable to flame and take 2 extra points of damage from any fire attack.
How is that different from 8 HD, +4 attack bonus, AC 12 (18 vs. energy weapons), 2d6 damage melee attack, takes +1d6 damage from fire attacks, and if it hits, inflicts an acid condition 1d6/turn unless fort save is made? Answer: it isn't, since I did a quick Cypher System to 5E conversion. Cypher System has much less math involved, and I can create challenges in my head instead of needing to endlessly reference books and try to balance encounters.
I don't need to spend hundreds of dollars on 5E monster books, waste hours reading them, or risk not having the monster I want for my game. Once you know Cypher, coming up with flavorful, rules-crunchy, deadly, and exciting monsters can be done in your head. Players never know what is next.
My game, gear, characters, and monsters can be flavored any way I want, and I am not limited to needing a 5E game that only does Mass Effect, Guardians, Traveller, Alien, Star Wars, Star Trek, or Heavy Metal. My game can be any of those: one, two, or all simultaneously.
Once you learn that vehicles can be handled just like monster-versus-monster combat (but using character skills), vehicle, mech, and starship combat becomes easy. I don't need lists of ships, vehicles, or mechs since I create them like monsters.
The Cyphers of the system also reflect all of the strange and fantastic devices you can find in sci-fi and go a long way toward enhancing the flavor. Subtle Cyphers are special one-use character abilities where you don't need to find an alien widget; you just have that inspiration stuck in your head and wait to fire it off when the moment is right. In my Road War game, I added "vehicle ciphers" to the cars, and they were fantastic and amazing one-shot abilities like a James Bond movie.
The pools of character abilities are what you fight against. This is a genius design since you are constantly managing resources and wondering how far you can push it before you need a rest - if you can get one. My Road War game I did last summer turned into a fantastic survival and resource management game where my courier in their junk delivery van would need to venture out into the desert to get jobs done, all while dealing with an ever-depleting pool of resources and very few chances to rest. Even resting is a resource - use it wisely.
Very few 5E games do resource management well. Too often, you get the default "complete party reset" every encounter, like a short rest can cure all ills. Entire games are built to combat the laissez-faire resource management of 5E, such as Low Fantasy Gaming, Shadowdark, and Level Up Advanced 5E. An entire cottage industry of "resource-constrained 5E" exists because 5E is so broken with implementing the concept.
We can't upset the players!
No one likes resource management!
Reset the party resources for the encounter! It is easier to balance the game!
D&D has been stuck in the Magic: the Gathering "reset the party" mode of play for 20+ years, and it is getting tiring. Every encounter is an MtG game, and we need to level-set resources to near-normal for the subsequent encounter to maintain balance. Wizards of the Coast tossed out resource management for accessibility.
Cypher System is deceptively simple. You look at it and say, "Everything is a generic 0-10 challenge? Where is the fun in that?" The game was created by decades of experience with the flaws of a d20 system, where all the cruft and wasted effort were cut away, and just the best parts kept. The focus stays on the characters and their resources - the best pieces of the game.
Cypher System does an end-run around 5E and tells you "none of the minutiae matters." None of it. You don't need lists and lists of anything for a setting. You flavor things yourself. The characters are where the focus should be. This is where 5E will be in about 20 years, if they can stop endlessly repeating the mistakes of the past.
And, of course, EN World has to derail this article by announcing a sci-fi setting and rules using Level Up A5E. This is on my must-have list and will compete directly with Cypher System. I have a lot of hope for this one and look forward to it.
White Star, I am keeping. It is a simple enough White Box, a straightforward and fast-playing game.
Level Up A5E sci-fi will be my 5E sci-fi game of choice.
Cypher System is my main "everything else" sci-fi game.
Starfinder? A whole other subject - we will get to that.