Anomalous origination of a coronary artery from the opposite sinus (ACAOS) is estimated to be present in 0.2-2.0% of the population. In the majority of individuals, ACAOS has no hemodynamic or prognostic implications, but in a minority of cases, typically where the anomalous coronary artery takes an interarterial course to reach its correct myocardial territory, it can precipitate ischemia and sudden cardiac death (SCD). With the growing use of CT coronary angiography (CTCA) in the investigation of ischemic heart disease, we can expect increasing rates of incidental detection of this anomaly. Although CTCA and magnetic resonance coronary angiography can effectively characterize these lesions anatomically, they fail to describe and quantitatively assess the basic defect that leads to coronary insufficiency, such as mural intussusception. The key challenge lies in the identification of which patients are at risk of SCD and, therefore, who should be offered corrective surgical or (potentially) percutaneous intervention. Conventional, noninvasive stress testing has limited sensitivity, but emerging, invasive stress tests, which utilize intravascular ultrasonography and measurements of fractional flow reserve, show the potential to provide more-accurate hemodynamic and prognostic assessment.