Recent medical advances suggest that the cellular natriuretic peptide/cGMP and NO/cGMP effector systems represent important signal transduction pathways especially in the cardiovascular system. These pathways also appear to be very interesting targets for the possible prevention of cardiovascular diseases. Exciting candidates for prevention include cGMP-dependent signaling networks initiated by natriuretic peptides (NP) and nitric oxide (NO) which are currently explored for their diagnostic and therapeutic potential. cGMP signaling contributes to the function and interaction of several vascular cell types, and its dysfunction is involved in the progression of major cardiovascular diseases such as atherosclerosis, hypertension and diabetic complications. This review will take a focussed look at key elements of the cGMP signaling cascade in vascular tissue. Recent advances in our knowledge of cGMP-dependent protein kinases (cGK, also known as PKG), the potential for assessing the functional status of cGMP signaling and the possible cross talk with insulin signaling will be reviewed.