This chapter discusses the presently known calcium (Ca2+)/calmodulin (CaM)-dependent protein kinases and some of their properties. To date, CaM kinase II is the only Ca2+)/CaM-dependent protein kinase known to phosphorylate a wide range of proteins and for this reason, it is sometimes referred to as the CaM-dependent multifunctional protein kinase or CaM-dependent multiprotein kinase. These properties, mainly established in vitro, together with the wide distribution of the kinase, suggest that CaM kinase II may be involved in the regulation of numerous physiological functions. The chapter summarizes the present knowledge of CaM kinase II with the particular emphasis on the molecular mechanisms involved in the regulation of kinase activity. It also reviews the literature concerning the putative physiological functions of the kinase. There is a great deal known about the in vitro properties of calmodulin (CaM) kinase II, both in terms of its substrate specificity and its regulation by CaM and autophosphorylation. Much of this characterization is based on the experiments performed with rat brain isozyme of CaM kinase II, although in the aspects examined to date isozymes of the kinase from other tissues appear to behave in a broadly similar manner in vitro. However, relatively little is known about the functions of the kinase in vivo. Investigation of the physiological role of the kinase in brain and other tissues will be a particularly exciting area for future work. The current knowledge of the in vitro properties and the availability of complimentary DNA (cDNA) clones will hopefully expedite this research.