There are gender differences in the presentation, diagnosis, and treatment of chest pain. When compared to men, women may have more atypical presentations of chest pain. In addition, current diagnostic tools are often not definitive regarding cardiac etiology for chest pain in women. The current diagnostic model of chest pain focuses on significant obstructions within the large coronary arteries as the cause for angina. Microvascular angina (MVA) represents an under-recognized pathophysiologic mechanism that may explain the apparent disparities and elucidate an etiology for the common finding in women of chest pain, ischemia on stress testing, and no obstructive coronary artery disease (CAD) on angiography in the presence of abnormal coronary reactivity testing. Endothelial dysfunction, estrogen deficiency, and abnormal nociception play a role in the pathophysiology of MVA. Treatments are targeted toward these underlying mechanisms. Recognizing the role gender and other pathophysiologic models of chest pain can play in the work-up and treatment of angina may identify a treatable cardiac condition, that would otherwise be discounted as non-cardiac in origin.