Serotonin (5-hydroxytryptamine, 5-HT) is a vasoactive amine and important regulator of vascular tone. Aberrant serotonergic activity contributes to vascular pathology in multiple cardiovascular disease states, including hypertension, diabetes, metabolic syndrome and chronic myocardial ischemia. Serotonin also plays a vital role in postoperative vascular dysfunction after cardioplegic arrest with cardiopulmonary bypass (CP/CPB). Perioperative microvascular dysfunction following CP/CPB manifests as an increased propensity for vasospasm or vasoplegia, with different effects in different tissue beds (coronary, skeletal muscle, pulmonary and systemic microcirculations). Given the importance of serotonin as a modulator of vasogenic responses, we present a selected narrative survey of the current literature concerning the effects of altered serotonergic activity on vascular dysfunction in the context of CP/CPB and other cardiometabolic diseases. This review begins with a discussion of normal serotonin biology and signaling pathways, then moves into disease-specific discussions covering five major areas of focus: metabolic syndrome, diabetes, hypertension, myocardial ischemia and CP/CPB.