Lymphedema is a chronic disorder that, in developed countries, occurs most commonly after lymph node dissection for cancer treatment. Although the pathophysiology of lymphedema is unknown, the disease is characterized histologically by fibrosis and abnormal adipose deposition. Clinical studies have provided evidence that obesity and postoperative weight gain are significant risk factors for the development of lymphedema. In fact, recent studies have shown that extreme obesity can result in markedly impaired lymphatic function and primary lymphedema. The aim of this Special Topic article is to review evidence linking obesity and lymphedema. In addition, the authors review recent studies that have analyzed the cellular mechanisms that may be responsible for this relationship, with a goal of highlighting areas of research that may have significant translational potential.