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Atherosclerosis and plaque disruption have a central pathological role in the majority of patients who present with an acute coronary syndrome (ACS), but non-atherosclerotic processes are also important contributors to a substantial number of ACS events and require different diagnostic and therapeutic strategies. In the absence of obstructive coronary artery disease, intravascular imaging techniques might be needed to delineate the underlying aetiology, together with a high index of suspicion for other important causes of ACS. In this Review, we discuss five non-atherosclerotic causes of ACS, including spontaneous coronary artery dissection, coronary artery embolism, vasospasm, myocardial bridging and stress-induced cardiomyopathy (Takotsubo syndrome). Important diagnostic findings, management strategies and prognostic data for these non-atherosclerotic mechanisms of ACS are reviewed.