Cyclic GMP (cGMP) and its effector kinase PKG regulate diverse cellular functions. In cardiac myocytes, cGMP is produced by soluble and particulate guanylyl cyclases (GCs), the former stimulated by nitric oxide and the latter by natriuretic peptides, and is hydrolyzed to inactive 5'-GMP by cGMP-phosphodiesterases (PDEs). cGMP-PKG modulates cardiac contractility, hypertrophy and remodeling, and exerts cardioprotection. Although early research efforts have mostly focused on cGMP synthetic pathways, recent studies have revealed that cGMP degradation controlled by PDEs plays a critical role in the physiological action of cGMP. Among several cGMP-PDEs, cGMP-specific PDE5 has been intensively investigated. Studies in experimental animal models and humans consistently demonstrate benefits from PDE5 inhibitors in various cardiac pathologies. Several clinical trials are ongoing or planned to test the efficacy of PDE5 inhibitors in human heart disease, including a large multicenter clinical trial (RELAX) led by the NIH evaluating sildenafil efficacy in heart failure with preserved ejection fraction. This review underscores the current understanding of cGMP-PKG signal regulation and its pathophysiological role in the heart, focusing on cardiac myocytes.