Chest pain stands as one of the most frequent patient presentations in the emergency department (ED). Despite established diagnostic algorithms for identifying several important causes of chest pain, such as acute myocardial infarction (AMI), aortic dissection, and pulmonary embolism, guidance on managing patients with recurrent chest pain, one of the top 3 reasons for repeated hospitalization in the United States, is less defined. The assessment of symptoms, serial ECG, and necrosis biomarkers plays a major role in patient management. Notably, the recently introduced high-sensitivity troponin T (hs-TnT) assay is helping to identify ischemia in patients previously undiagnosed by conventional testing. In Europe, with the use of this assay for over a decade, the identification of patients with AMI has substantially increased, particularly of patients with type 2 AMI, which is seen in the absence of atherosclerotic obstruction of the epicardial coronaries on angiography. Use of hs-TnT is in particular relevant in women, in whom the use of a sex-specific threshold for elevated hs-TnT has almost doubled the diagnosis of AMI. With the advent of the hs-TnT assay in the United States in 2017, a similar phenomenon is expected. Thus, it is important to learn from the European experience and to develop sex-specific nuanced algorithms for the evaluation of additional causes of myocardial ischemia/necrosis, such as coronary artery vasomotor disorders and coronary microvascular dysfunction. The latter has a high prevalence among symptomatic women presenting to the ED, a group in whom recurrent chest pain is common. This commentary describes the tools available for diagnosing epicardial- and non–epicardial-related myocardial ischemia in patients with recurrent chest pain in the ED setting. A sex-specific, nuanced approach applied to select groups of patients being observed in the ED has the potential to reduce admissions and to allow for the initiation of timely, appropriate medical treatment and outpatient follow-up in an at-risk population. The costs and availability of advanced diagnostics may pose some limitation to the widespread adoption of such protocols. © 2018 Elsevier Inc.