Signaling cascades initiated by nitric oxide (NO) and natriuretic peptides (NPs) play an important role in the maintenance of cardiovascular homeostasis. It is currently accepted that many effects of these endogenous signaling molecules are mediated via stimulation of guanylyl cyclases and intracellular production of the second messenger cGMP. Indeed, cGMP-elevating drugs like glyceryl trinitrate have been used for more than 100 years to treat cardiovascular diseases. However, the molecular mechanisms of NO/NP signaling downstream of cGMP are not completely understood. Recent in vitro and in vivo evidence identifies cGMP-dependent protein kinases (cGKs) as major mediators of cGMP signaling in the cardiovascular system. In particular, the analysis of conventional and conditional knockout mice indicates that cGKs are critically involved in regulating vascular remodeling and thrombosis. Thus, cGKs may represent novel drug targets for the treatment of human cardiovascular disorders.