Chest pain with normal coronary arteriograms represents a major diagnostic and therapeutic challenge to contemporary cardiology. Cardiac syndrome X (CSX), defined as typical angina-like chest pain, a positive response to exercise stress testing and normal coronary arteriograms, encompasses patients with a variety of pathogenic mechanisms. Cardiac ischemia has been documented in approximately 25% of CSX patients and is associated with endothelial dysfunction and microvascular vasodilator abnormalities. Increased endothelin-1, a powerful vasoconstrictor, has been suggested to play a pathogenic role. There is a high prevalence of postmenopausal women with CSX and thus estrogen deficiency has also been proposed to represent a possible pathogenic mechanism. Inflammatory mechanisms and endothelial dysfunction at the coronary microvascular level appear to be important in the pathogenesis of CSX. Treatment with agents that have protective effects on the vasculature and also anti-inflammatory properties, such as statins and angiotensin-converting enzyme inhibitors have been effective in improving both symptoms and electrocardiographic signs of myocardial ischemia in patients with CSX. This review discusses the roles for endothelial dysfunction and inflammation in the pathogenesis of CSX, as well as the potential therapeutic implications of these mechanisms.