Perivascular adipose tissue (PVAT) directly abuts the lamina adventitia of conduit arteries and actively communicates with the vessel wall to regulate vascular function and inflammation. Mounting evidence suggests that the biological activities of PVAT are governed by perivascular adipocytes, a unique class of adipocyte with distinct molecular and phenotypic characteristics. Perivascular adipocytes surrounding human coronary arteries (pericoronary perivascular adipocytes) exhibit a reduced state of adipogenic differentiation and a heightened proinflammatory state, secreting ≤50-fold higher levels of the proinflammatory cytokine monocyte chemoattractant peptide-1 compared with adipocytes from other regional depots. Thus, perivascular adipocytes may contribute to upregulated inflammation of PVAT observed in atherosclerotic human blood vessels. However, perivascular adipocytes also secrete anti-inflammatory molecules such as adiponectin, and elimination of PVAT in rodent models has been shown to augment vascular disease, suggesting that some amount of PVAT is required to maintain vascular homeostasis. Evidence in animal models and humans suggests that inflammation of PVAT may be modulated by environmental factors, such as high-fat diet and tobacco smoke, which are relevant to atherosclerosis. These findings suggest that the inflammatory phenotype of PVAT is diverse depending on species, anatomic location, and environmental factors and that these differences are fundamentally important in determining a pathogenic versus protective role of PVAT in vascular disease. Additional research into the mechanisms that regulate the inflammatory balance of perivascular adipocytes may yield new insight into, and treatment strategies for, cardiovascular disease.