Nitric oxide (NO) participates in the regulation of the daily activities of cells as well as in cytotoxic events. Elucidating the mechanism(s) by which NO carries out its diverse functions has been the goal of numerous laboratories. In the cardiovascular system, evidence indicates that NO mediates its effects via an activation of soluble guanylyl cyclase (sGC). In other tissues, it is not clear if sGC is an exclusive target for NO or what the functions of cGMP might be. It is also unlikely that the diversity of NO actions is explained solely by changes in cGMP. This review focuses on the evidence that NO modulates cAMP signalling, with specific attention to the effects of NO on adenylyl cyclase (AC) as the target of NO regulation.