Compartmentation plays a critical role in determining the specificity and efficacy of signaling by adenosine 3',5'-monophosphate (cAMP) and other second messengers. It has become apparent that all of the protein components of the cAMP signaling pathway are subject to regulation and may be localized to particular subcellular compartments. This Perspective discusses recent research concerning the importance of cAMP phosphodiesterase localization in cAMP signaling, functional implications of the organization of this pathway's protein components into macromolecular complexes, and common themes in the compartmentation of cAMP- and Ca2+-mediated signaling pathways.