Some spoilers incoming.
1. Find a middle road between ME1's RPG elements and ME2's RPG elements. ME1 was too cluttered, the skill system was full of useless stuff, the inventory was atrocious. While I do like the ME2's mechanics better, making them a bit more complex would enrich the game without making it cluttered.
2. Maintain the same level of character writing that ME2 had. Maintain the same level of main plot quality ME1 had. ME2's main story isn't bad, but it lacks focus, a proper antagonist and a good conclusion. On the other hand, the party members in ME2 are overall a big improvement. Liara, Kaidan and Ashley were quite flat. Compare them to Jack, Samara, Thane and especially Mordin (I adore his rendition of Gilbert and Sullivan [http://www.youtube.com/watch?v=uXiU6kiq_Ms]). Even the good ones from ME1 are better in ME2 (Garrus, Tali).
3. Make the shooting even better. ME2's gunplay is a vast improvement over the first game, but there's still polish to be added, AI to be improved, etc. Also, appropriate level design is critical as well.
4. Let us customize our decisions when making a new character! This should be added to ME2 as well. Players starting new characters should be allowed to make at least some of the more important decisions from the previous game(s). Veterans who import their chars should get more and better options, of course.
5. Don't fuck up the plot threads from ME1&2! The plot of ME3 is obvious: Reapers attack, Shepard gathers the various forces in the galaxy to fight on his side. There are tons of possibilities here to tie in with the previous games and some are even hinted at in ME2. Did you spare the Rachni queen? In ME2 she tells you she'll be there to back you up when the time comes. Did the Quarians go to war with the Geth? Did they win? Did you make the Heretics join back with the Geth or did you destroy them? Who's running the Council? The list goes on. All of this and more could determine who can join you and how much they can help you. Granted, Bioware has a phobia when it comes to potentially redundant content that players might miss entirely, but if they work at it they could make an epic the likes of which haven't been seen before...