The biological molecule NO and its cyclic nucleotide effector molecule cGMP, are involved in a variety of biological systems. This article reviews evidence supporting a role for these molecules in signal transduction. Over the last 10 years, it has become evident that these molecules are important in Ca2+ regulation, particularly in excitable cells. In these cells, cGMP-dependent mechanisms appear to both directly and indirectly regulate Ca2+ transport. Until recently, reports of the actions of cGMP in non-excitable cells have been contradictory, presenting a confusing plethora of effects. In these cells, the cGMP-Ca2+ regulation pathway appears to be concentration-dependent, possibly representing a negative feedback mechanism. Ca2+ entry appears to be activated when low concentrations of cGMP are present, and inhibited at higher concentrations. The role of cGMP in Ca2+ regulation in non-excitable cells has been largely overlooked and further investigation of this issue may provide clues as to the nature of various unknown components that induce Ca2+ entry into these cells.