With the states of Colorado and Washington being the first to enact legalization of marijuana laws, and the federal government having solidified its power to criminalize marijuana through the Supreme Court's 2005 decision in Gonzales v. Raich, it seems that the issue will center around whether the federal government has the power to coerce state law enforcement to enforce the federal law.
Another thing that might happen is that legalization will eventually be pursued by all of the states, and the federal law will be repealed without a fight.
In the words of Harvard Law professor, Noah Feldman, in his Bloomberg opinion piece:
If the federal ban on marijuana is here to stay, that leaves the question of the federal government’s capacity to enforce its laws. In practice, the feds cannot go after small- time growers in any serious way, to say nothing of users. Could they enlist state law enforcement to enforce federal law? The health-care decision says that Congress cannot threaten the withdrawal of major funding, and earlier precedent involving gun control says that the federal government may not commandeer state resources. So any federal effort to make states enforce antidrug laws would be subject to legal challenge.
The upshot is that de facto legalization of marijuana might occur even if the federal government never takes part. There will be no dramatic headline, as there would be for a same-sex marriage decision. But the will of the people will prevail, and the Supreme Court will not stand in the way.