Oh you could certainly do a lot of tricks to get certain effects. Separate shadow passes would probably be the easiest. So you would render your image without shadows, and then slowly 'fade' them in/out depending on what you wanted to do. Normal Maps are also very useful for faking 3D lighting (as in Pillars Of Eternity).
The biggest issues with 2D art isn't necessarily the amount of 'tricks' you can use to get things done (they have been around for a lot longer than 3D!), but A) The extra amount of additional assets you need to do these tricks, and B) The skills of the individual artists.
It is also very difficult to alter content once its done in 2D - a LOT more difficult than in a 3D engine.
You also have the ability to spread your skills across your artists.
In a 3D game you could have an incredibly skilled artist making 3D Assets, and pass them onto other artists who arent necessarily up to that same level. Those artists can then use those assets and create a piece of work that is probably very close to what the original artist would have done (at least from a visual standpoint). You have the freedom of using people who are actual level designers/gameplay programmers able to adjust art and environments 'on the fly' while they work, making the game feel a lot tighter.
Again, the solution to this is a tile based system, but then you are limited in being able to do physics simulations. A 2D/3D hybrid is the best solution. This is a gameplay demo of The Whispered World 2 where they are using a 2D/3D hybrid solution of camera projection, 2D painted areas and 3D models.
http://www.youtube.com/watch?v=sqO5lmK1zK0
So it CAN be done - but it requires a huge input from your artists who require multiple specialities across the board.
I will ALWAYS do 2D Artwork because its my preferred medium - but I would never do the kind of game they are attempting with Dead State! Now a Fallout style game...that can be done.. :D