Numerous pharmacological and physiological agents acting via either cAMP- or cGMP-mediated impact the activities of cells of the cardiovascular system. While most define cAMP and cGMP signaling systems as separate and independent, recent advances in our understanding of cyclic nucleotide signaling, and more specifically, of the roles which cyclic nucleotide phosphodiesterases (PDEs) play in these events, have altered this view. In this short chapter, I will review the data identifying expression of several PDEs in cells of the cardiovascular system. In addition, I will review the data that identify PDEs as enzymes capable of allowing integration between cAMP and cGMP signaling in cells, and propose that cAMP and cGMP signaling systems can represent parallel and interdependent signaling systems. Moreover, I will propose that cGMP-mediated effects on the activities of variants of the Phosphodiesterase 2 (PDE2), PDE3 and PDE5 families may act to coordinate linkage between cAMP and cGMP signaling in these cells.