▪ Abstract Calmodulin (CaM) is an essential protein that serves as a ubiquitous intracellular receptor for Ca²⁺. The Ca²⁺/CaM complex initiates a plethora of signaling cascades that culminate in alteration of cellular functions. Among the many Ca²⁺/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 Ca²⁺/CaM interaction with and regulation of its target enzymes. Gene transcription has been chosen as the functional endpoint to illustrate the recent advances in Ca²⁺/CaM-mediated signal transduction mechanisms.