Calcium entry blockers (CEBs) are a new class of drugs which have been pushing back the frontiers of science and medicine for almost two decades. This report reviews some of the wealth of chemical, biological and clinical data describing the discovery and development of these compounds. The prototypes are verapamil, diltiazem and nifedipine. These three compounds, of very different chemical structure, share a common inhibitory action on the influx of extracellular calcium and have been widely studied as probes into the role of calcium in excitation-contraction and excitation-secretion coupling in cell life and in cell death. In addition, these agents have proven highly effective as therapeutic agents in cardiovascular disease, most notably in angina pectoris, peripheral and cerebral vascular disease and hypertension. The scientific importance, therapeutic benefit and marketing potential of these compounds have caused an explosion of scientific literature describing their effects in many preclinical and clinical settings. More than twelve different compounds have been marketed in the over 25 years since the first molecule later designated CEB prenylamine was introduced. Over 50 additional new compounds, however, are currently in various stages of development. The definitional characteristics of these compounds suggest a certain predictability of their biological profile but their therapeutic usefulness varies widely dependent upon their physical properties, net hemodynamic effects, duration of action and incidence of side effects. CEBs appear uniquely suited to the treatment of the underlying complexity of cardiovascular disease.