Over the past few years, a wealth of biochemical and functional data have been gathered on mammalian cGMP-dependent protein kinases (cGKs). In mammals, three different kinases are encoded by two genes. Mutant and chimeric cGK proteins generated by molecular biology techniques yielded important biochemical knowledge, such as the function of the NH(2)-terminal domains of cGKI and cGKII, the identity of the cGMP-binding sites of cGKI, and the substrate specificity of the enzymes. Genetic approaches have proven especially useful for the analysis of the biological functions of cGKs. Recently, some of the in vivo targets and mechanisms leading to changes in neuronal adaptation, smooth muscle relaxation and growth, intestinal water secretion, bone growth, renin secretion, and other important functions have been identified. These data show that cGKs are signaling molecules involved in many biological functions.