Under physiologic conditions, epicardial arteries contribute minimally to coronary vascular resistance. However, in the presence of endothelial dysfunction, stimuli that normally produce vasodilation may instead cause constriction. Examples include neural release of acetylcholine or norepinephrine, platelet activation and production of serotonin and thrombin, and release of local factors such as bradykinin. This shift from a primary endothelial-mediated vasodilator influence to one of endothelial dysfunction and unchecked vasoconstriction is precisely the milieu in which coronary vasospasm is observed. This condition, which typically occurs during periods of relatively sedentary activity, is associated with focal and transient obstruction of an epicardial arterial segment resulting in characteristic echocardiographic changes and symptoms of myocardial ischemia. This review highlights the current understanding of mechanisms regulating the coronary circulation during health and examines the pathophysiologic changes that occur with coronary spasm. Genetic and other predisposing conditions are addressed, as well as novel therapies based on recent mechanistic insights of the coronary contractile dysfunction associated with coronary spasm.