Pavlovian cues associated with reward exert a powerful motivational influence on the performance of goal-directed actions. This motivational process depends critically on the ventral striatum, although little is known about the cellular and molecular mechanisms that mediate it. In the current experiments we examined the role of calcium calmodulin-dependent kinase II (CaMKII) by using transgenic mice that express a constitutively active form of this kinase. We found that controlled expression of active CaMKII in the striatum did not affect learning but did impair the motivation of goal-directed actions by Pavlovian cues associated with reward. Mutant mice learned to lever press for reward, remained sensitive to outcome devaluation and contingency degradation manipulations, and were able to acquire Pavlovian responses to cues paired with reward. However, Pavlovian cues were completely unable to motivate lever pressing in mutant mice. This was true even in mice trained with the CaMKII transgene turned off and then tested with it turned on. We were also able to suppress transgene expression in impaired mutants and fully restore the motivational effects of reward cues in these animals. Therefore, the current experiments demonstrate that normal CaMKII activity in the striatum is essential for the motivational effects of reward cues on goal-directed actions.