Intracellular cAMP and cGMP levels are increased in response to a variety of hormonal and chemical stimuli; these nucleotides play key roles as second messenger signals in modulating myriad physiological processes. The cAMP-dependent protein kinase and cGMP-dependent protein kinase are major intracellular receptors for these nucleotides, and the actions of these enzymes account for much of the cellular responses to increased levels of cAMP or cGMP. This review summarizes many studies that have contributed significantly to an improved understanding of the catalytic, regulatory, and structural properties of these protein kinases. These accumulated findings provide insights into the mechanisms by which these enzymes produce their specific physiological effects and are helpful in considering the actions of other protein kinases as well.