Aspirin is one of the most widely used medications across the global healthcare system and is the foundation in treating ischemic heart disease, as well as secondary prevention for ischemic and valvular heart disease. Challenges arise in treating patients with cardiovascular disease who have concomitant aspirin intolerance. Through an extensive review of the literature, we provide a comprehensive background on the pharmacology of aspirin, the mechanisms behind aspirin intolerance, the importance of aspirin in cardiovascular disease, and the management of aspirin intolerance in both acute coronary syndrome and stable coronary artery disease. Our review includes a multidisciplinary approach from the internist, allergist/ immunologist, and cardiologist when evaluating this important patient population.