After Time To Kill and Zero Hour, it's another Duke Nukem game involving time travelling in its scenario: The Earth Defense Forces are monitoring the future, using a time machine, but all people they send there did not come back and lost contact. Thus they send in Duke Nukem to save the day. As he gets there, Duke finds out that aliens have invaded Earth (*again*) and do experiments on Earth's women. This of course calls for another round of alien-ass-kicking.
Similar to Manhattan Project, the game is basically a 2D-sidescrolling shoot'em up/ platformer, but the environment is modeled with 3D graphics, which is for example used for pan shots or changing the axis of the path you walk along. To spice up the gameplay a bit, there are some 1st person and 3rd person shooting sequences included.
Duke Nukem: Critical Mass was originally to be the first part in the planned Duke Nukem Trilogy for the Nintendo DS and Sony PSP alongside the two planned sequels, Duke Nukem: Proving Grounds and Duke Nukem: Chain Reaction which were subsequently cancelled.