Since the isolation and characterization of cAMP in early 1957, several enzymatic and chemical synthetic procedures have been developed to provide cAMP and various cyclic nucleotide analogs. The synthesis of cAMP and 2′-deoxy-cAMP by bacterial fermentation is of current commercial interest as a low cost source of nucleoside 3′,5′-cyclic phosphates. In this chapter, the improvements made over the years on the original synthesis of cAMP (via DCC mediated cyclization of AMP) by employing different coupling reagents, transesterification of “active” phosphates of AMP and isolation techniques are reviewed. By far the largest number of cyclic nuceotide derivatives have been prepared by the chemical transformation of parent cAMP and cGMP itself. A substantial number of cAMP derivates have been synthesized in which there are substituent modifications of the purine base, and structural modifications of the carbohydrate moiety and the cyclic phosphate moiety. Representative examples of cyclic nucleotide analogs related to cAMP, such as 1-deazapurine, 3-deazapurine, 7-deazapurine, 2-azapurine, 8-azapurine, formycin, and l,N6-ethenoadenosine cyclic phosphates, are treated in some detail. Description of some of the more important methods currently being used for the preparation of cyclic nucleotides related to cGMP and pyrimidine cyclic nucleotides are presented. Detailed information about the hydrolytic and spectral properties of cyclic nucleotides are also included. Due to the recent availability of an enormous number of synthetic cyclic nucleotide analogs, considerable success has been achieved in obtaining potent phosphodiesterase (PDE) inhibitors with greater tissue specificity. We now have cyclic nucleotides which are more resistant toward cellular PDE than the parent cAMP and, consequently, survive intracellularly long enough to provide an increased physiological response. An effort has been made, in the present chapter, to show that future cyclic nucleotide chemistry has the potential to provide highly potent cyclic nucleotide derivatives, which may have a significant effect on uncontrolled cellular proliferation, the immune response, asthma, the central nervous system, gastrointestinal function and other physiological responses characteristic of the natural cyclic nucleotides.