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Many years after the events in the Mega Man Zero series, humans and Reploids (humanoid robots) have at last found peace. Two humans, Vent and Aile, work for a delivery company called Giro Express. After being ambushed during a delivery, they come in contact with something called 'biometal', which transforms them into the Maverick Hunter, X. Using their new powers, they decide to work for a group called "The Guardians", who protect civilians from Maverick attacks.

Mega Man ZX is a side scrolling platformer for the Nintendo DS. While the gameplay is similar to the Mega Man X series, in that you find powerups to increase your health meter, gain subtanks to store surplus energy when needed, and gain new abilities such as swimming and flight through acquiring boss powers, the art style is more similar to the Mega Man Zero series of games.

As players progress through the game, they gain the power of different types of "biometal", which gives them robotic weaponry and abilities. Different situations require different biometal suits, and sometimes (such as in civilian areas), it's best to return to your human form so that you can make your way through areas without being hassled. New models of biometal can be acquired from boss enemies. While you can hit their weak spots for more damage, it's actually beneficial not to, as the more damage you do to the weak spot results in more repairs that you need to make to the biometal later.