Calmodulin (CaM) is an essential protein that serves as a ubiquitous intracellular receptor for Ca(2+). The Ca(2+)/CaM complex initiates a plethora of signaling cascades that culminate in alteration of cellular functions. Among the many Ca(2+)/CaM-binding proteins to be discovered, the multifunctional protein kinases CaMKI, II, and IV play pivotal roles. Our review focuses on this class of CaM kinases to illustrate the structural and biochemical basis for Ca(2+)/CaM interaction with and regulation of its target enzymes. Gene transcription has been chosen as the functional endpoint to illustrate the recent advances in Ca(2+)/CaM-mediated signal transduction mechanisms.