Although differences diminish with age, outcomes are overall worse for women compared to men who present with suspected acute coronary syndrome. The reasons for this discrepancy are multifactorial, including sex-related differences in atherosclerosis biology and fluid dynamics, as well as a premature conclusion by providers that chest pain must be noncardiac in the absence of obstructive coronary artery disease. In this review of existing literature, we explore the diverse differential diagnosis in this unique set of patients. Especially in women with persistent symptoms, absence of occlusive disease should prompt consideration for subangiographic plaque disruption, epicardial or microvascular endothelial dysfunction, transient neurohormonal imbalance predisposing to Takotsubo cardiomyopathy or spontaneous coronary artery dissection, underlying systemic inflammatory conditions, thromboembolic disease, myocarditis, and sequelae of congenital heart disease. As always, a thorough history and attentive physical exam will help guide further work-up, which in many cases may warrant noninvasive imaging, such as contrast-enhanced echocardiography, cardiac magnetic resonance imaging, or positron emission tomography, with their respective means of measuring myocardial perfusion and myocardial tissue pathology. Lastly, intracoronary imaging such as intravascular ultrasound and optical coherence tomography and invasive diagnostic methods such as coronary reactivity testing continue to add to our understanding that what appear to be atypical presentations of ischemic heart disease in women may in fact be typical presentations of pathologic cousin entities that remain incompletely defined.