One of the major mediators of calcium action in neurons is the multifunctional calcium/calmodulin-dependent protein kinase (CaM kinase), an enzyme with the capability of directly regulating its own activity by autophosphorylation. To assess the involvement of CaM kinase in experience-dependent behavior in an intact animal, we have designed a specific peptide inhibitor of CaM kinase and made transgenic Drosophila that express it under control of an inducible promoter. These flies fail to learn normally in two behavioral plasticity paradigms: acoustic priming, a nonassociative measure of sensitization, and courtship conditioning, a measure of associative learning. The magnitude of the learning defect in the associative paradigm appears to be proportional to the level of expression of the peptide gene in the two transgenic lines and can be increased by heat shock induction of gene expression. These results suggest that CaM kinase activity is required for plastic behaviors in an intact animal.