While I really love the ME, I do have a few suggestions for the sequel.
1) Garrus returns as your Spectre apprentice. He said he was going to go back to C-Sec and re-apply for Spectre training, so let's see where that goes.
2) I'm pretty sure the Asari Consort is a Shadow Broker, so have a nice long side-quest for that.
3) Shepard should split from the alliance to more fully embrace his Spectre duties. He should be given an honourary C-Sec rank (Executor sounds nice) and the crew of the Normandy should be made up of plenty of other races.
4) Now that Shepard isn't with the Alliance anymore (assuming you go with suggestion #3) and probably doesn't have to look so polished, you could probably have a lot more variation in the character creator/modify an existing model with new options. One could conceivably go nuts with colours of eyes and hair (consider cosmetic genetic manipulation would make thinks like red eyes and silver hair possible, or even heterochromia iridium).
5) Ditch the Mako. Instead have some small mecha (Arm-slaves from Full Metal Panic come to mind as a good starting point because their "lambda driver" could give the thought of biotics an a mecha scale and the tech is definitely not beyond what is present in the ME universe). Three small mecha could slide out of the Normandy's doors just like the Mako does now. There are plenty of customization options there.
6) We need an A.I. party member to add another dimension to what should definitely be happening with the Geth, just like Wrex added something to Virmire. How about a ship-board A.I. named Aegis. She could also have an engineer avatar robot for missions. It's a good character to pivot some stories on concerning the Geth. I'll have to outline my thoughts on this option later in more detail, but there's a logic to it.
7) Biotics should have a little more offensive capability. Warp should evolve into some sort of projectile pulse, maybe like a Hadouken or a quigong strike from the manga Tenjhou Tenge.
8 ) Limit the amount of returning characters. Liara should commit her life to researching everything on Ilos. Tali should go back to the Quarian fleet and spend the next few years decoding those files you gave her. Wrex should only be around if you have a cure for the genophage, which he can use to unite his people. I doubt Kaiden or Ashley really have much more story to tell, so we can brush them aside easily. Priesly should go, but Chakwas and Joker should stay. All that said, it would be cool to have the old removed characters get nice cameos. Bring in one of those Salarian commandos to replace Ashley, and a HOT freelancer human from the Terminus to round out the attitude spectrum on the Normandy. I've actually come up with some good stories for these new characters.
9) A quest to cure the genophage should be an option at some point. Also, keep running with the Cerberus story.
10) The look of armours and weapons should be more varied. Nothing crazy, just cool. Bungie had a nice design thing going with their Halo 3 multiplayer armour permutations, but I'm sure you guys could blow them out of the water.
11) A higher level cap then 60. Ideally (but it's probably not really doable), have the chance to have every skill on one character and max them all out.
12) Spectres should have access to some cool (but not wierd) genetic mods/cybernetic enhancements. I'm thinking a little Ghost in The Shell here. I'm aware there are laws prohibiting certain genetic augmentations, but since Spectres are above the law...
13) My wife wanted this really badly, but female Shepards should be able to romance Garrus. Don't ask me why, but she thinks Turians are super-hot!
14) I'd like to see some good examples of design differences in the technology of different races. At some point I should be able to clearly differentiate design doctrines, look at a random piece or tech and instantly know who made it.
15) Squad control should allow you to command members separately, as well as together.
16) All the issues with graphics, A.I., sound and everything else are fixable. Make us drool for it while you really polish your work. Keep us occupied with podcasts, pics, vids, blogs and everything else you can think of to make a fan squeal, but don't rush on our account. We will appreciate you all the more that way. Make sure to use the HDD install ability of the NXE.
17) More mini-games with more variety. There's an old Star Trek FPS that had a cool system bypass mini-game, so maybe something like that.
18) Grenades were odd. I'd like them to have different settings. The standard setting would be the same as it is now, but you could also set it to sticky proximity and maybe add a very slight homing option to the primary option. Bend it like you would a frisbee or soccerball.
19) I'm not screaming "brink back lightsaber melee combat!" like some deranged Star Wars fan (no hate brothers, its all love), but maybe a re-examination of the melee options in ME is advisable. Military vibro-knives, bayonets and some martial arts action COULD be pretty cool.
20) The Codex should have vids connected to some of its entries, and there should be a master codex viewable from the game selection screen (in extras maybe), because even though each time I start a new character it clears the in-game codex, I'd still like access to the entries I've already unlocked.
21) Seth Green could be asked to colour a little of the more humourous script. Not that the current team isn't doing a fantastic job (because they ARE), but Seth is a master of comedy and might be able to add one or two things. He's already on as Joker (wonderful job on all the voice acting BTW), why not.
22) Normandy should get an overhaul. Change it a little in 2 and again a little in 3.
I took these from a post I made on the Mass Effect offical boards. Check the link for other suggestions and responses from other players. I managed to get 4 pages of good discussion going. I did remove some of my suggestions and change a few others slightly for this post becaause I've had quite some time to think them over. Let me know what you all think!