Adipose tissue (AT)-derived factors contribute to the regulation of cardiovascular homeostasis, thereby playing an important role in cardiovascular health and disease. In obesity, AT expands and becomes dysfunctional, shifting its secretory profile toward a proinflammatory state associated with deleterious effects on the cardiovascular system. AT in distinct locations (ie, adipose depots) differs in crucial phenotypic variables, including inflammatory and secretory profile, cellular composition, lipolytic activity, and gene expression. Such heterogeneity among different adipose depots may explain contrasting cardiometabolic risks associated with different obesity phenotypes. In this respect, central obesity, defined as the accumulation of AT in the abdominal region, leads to higher risk of cardiometabolic alterations compared with the accumulation of AT in the gluteofemoral region (ie, peripheral obesity). The aim of this review was to provide an updated summary of clinical and experimental evidence supporting the differential roles of different adipose depots in cardiovascular disease and to discuss the molecular basis underlying the differences of adipose depots in the regulation of cardiovascular function.