To me, Microsoft is going to have the most difficult path next generation for several reasons. Of course, these reasons are based on current speculation, but hey that's all we've got.
1) They will not have the technology advantage. By far, this was their biggest key this generation. Without it, and if fact, potentially being in 3rd place in the horsepower war will make it difficult to maintain their current fans who clearly want the most powerful system.
2) They will come out first and they will have to face the hype of the other two systems much like the dreamcast. It's very difficult to fight a ghost and people like to wait for more options to show up before they make the "big" decision.
3) Sony will have an Xbox Live "like" service from day 1. Again, it may not be as advanced as Microsoft's, but it will again counter one of their key advantages.
4) Microsoft, as far as consumers go, by far has the weakest 1st party lineup. For casuals you've got Halo and that's it. RSC, PGR, MechAssault, etc may be great games, but as far as sales go, they haven't become huge franchises like Mario, Zelda, Pokemon, Gran Turismo, Twisted Metal, J&D, R&C, SOCOM,etc.
5) Microsoft failed to make an inroads into Japan with the exception of Tecmo. While Japan may not be the "end all be all" of gaming anymore, you cannot simply have a 0% contribution of games like Final Fantasy, Metal Gear Solid, Resident Evil, Tekken, etc.