The cyclic nucleotide cGMP and its corresponding activated kinase cGK-1 serve as a counterbalance to acute and chronic myocardial stress. cGMP hydrolysis by several members of the phosphodiesterase (PDE) superfamily, PDE1, PDE2, and PDE5, regulate this signaling in the heart. This review details new insights regarding how these PDEs modulate cGMP and cGK-1 to influence heart function and chronic stress responses, and how their inhibition may provide potential therapeutic benefits.