The literature concerned with studies of the occurrence and function of the cyclic nucleotides in blood vessels is reviewed. Emphasis is placed on the critical evaluation of the evidence which relates to the hypothesis that cyclic nucleotides mediate the effects of drugs and neurotransmitters on vascular contractility. The hypothesis that cyclic AMP mediates vasodilation, especially that induced by β-adrenergic relaxation, is supported by many experimental approaches, but it is concluded that the evidence remains unconvincing based on the criteria established for such a mediator role. Possible sites of action of cyclic AMP are discussed. The demonstrated action of cyclic AMP on vascular membrane electrophysiology and calcium ion pumps are reviewed as possible causes of relaxation. The role of both nucleotides in vascular disease, especially hypertension is discussed. Finally the needs for further research in this area are suggested.