Millions of Americans are afflicted by obesity and type 2 diabetes mellitus. Obesity is characterized by increased body adiposity and leads to insulin resistance. Paradoxically, some conditions that are characterized by a paucity of fat also cause insulin resistance, namely the syndromes of lipoatrophy (Fig. 1). The resemblance between the metabolic abnormalities of these two extreme states of adiposity emphasizes the importance of fat tissue in energy homeostasis. This review focuses on the syndromes of lipodystrophy and lipoatrophy that are at the lean extreme of the spectrum and which are characterized by near-complete absence of fat.