Nitric oxide donors have been commonly used in the therapy of cardiovascular disease for more than 150 years. In spite of this longevity and the popularity of their use, it appears somewhat paradoxical that there is no current consistent use among cardiologists, as to both their indications and their optimal mode of administration. In part this results from their contradictory pharmacodynamics: when given acutely, their effectiveness is undisputable; however, their long-term efficacy is potentially limited by the development of tolerance and the induction of endothelial dysfunction, which may have negative prognostic implications. This review reports recent biochemical and pathophysiological acquisitions, re-examines the role of nitrates and other nitric oxide donors in cardiovascular medicine, comparing and commenting on international guidelines; and highlights areas of uncertainty, where more clinical research with these drugs would still be warranted.