Most effects of the signaling molecule nitric oxide (NO) are mediated by the stimulation of NO-sensitive guanylyl cyclase (GC) and the subsequent intracellular increase in cGMP. Two isoforms of NO-sensitive GC have been identified to date that share regulatory properties but differ in their subcellular localization; the more ubiquitously expressed alpha1beta1 heterodimer, and the alpha2beta1 isoform mainly expressed in brain. New activators of NO-sensitive GC have been identified which may have beneficial pharmacological effects in cardiovascular diseases. In intact cells, NO-induced cGMP signaling not only depends on cGMP formation but is also critically determined by the activity of the enzyme responsible for cGMP degradation, e.g. phosphodiesterase 5 (PDE5). Sustained activation of PDE5 by cGMP has been identified as the mechanism responsible for the recently observed feedback inhibition within NO/cGMP signaling. Moreover, tuning of PDE5 activity may also represent a regulatory link to mediate cross talk between NO-induced and natriuretic peptide-induced cGMP signaling in general.