Myocardial infarction in young adults is, in practice, a diagnosis of exclusion. Given the fact that most of the patients with sickle cell disease are young and have predisposition to painful crisis, they are often overlooked for myocardial infarction. These patients often have few or no traditional risk factors for coronary artery disease, and risk stratification tools such as the Thrombolysis in Myocardial Infarction (TIMI) and Global Registry of Acute Coronary Events (GRACE) models place these patients at low risk. Nonspecific changes on electrocardiogram are of little diagnostic value. Myocardial infarction is very often a missed diagnosis in patients with sickle cell disease. Diagnostic criteria, potential mechanisms, and management for acute myocardial infarction in patients with sickle cell disease are discussed.