1) You must always have an active internet connection
2) You must use EA's origin service (known for it's spyware and security holes)
3) Terraforming is officially out
4) Maximum sized maps are only the size of a SimCity 4 medium map, and to put the icen on the cake, you can no longer build outside your city area (the region is off limits!), so in other words you are limited to building a small city/town (no more sprawling metropolises like Sim City 4).
5) You cannot control regional mass transit anymore, and are restricted by pre-defined road connections.
6) Even if you want to play solo mode, you are still online, still a part of the online world, and your city will still be influenced by the virtual online global market. No more single player sandbox, this is a multiplayer game like it or not! [UPDATE: Maxis have recently confirmed that you do not need to participate in the global market if you are playing in solo mode. However, you are still bound by the other multiplayer rules and restrictions, as far as we can confirm at this stage]
7) Modding is out, atleast for the time being. Personally I don't see how Maxis can include mod support in an MMO game anyway, because mods would upset the game balance, and game balance is usually essential in an MMO game + DLC's would make an attractive profit earning alternative to communty mods
8 ) If you get some troll set up a city next to your city, and he decides to create lots of pollution or crime, your city will ofcourse pay the consequences
9) The game is very expensive, and i'm sure there will be many more DLCs to come to "fix" the game, and ofcourse earn EA an extra bit of profit from us consumers.
10) Your saved game will be located on an EA server. If EA decide to shut down the servers due to lack of profit, say goodbye to your cities! EA have a history of doing this with other games, and Maxis have blatantly ignored all questions regarding this matter.
11) No direct control of zoning, this is now controlled by the type of road used
12) No more farms or agricultural zones