Hyperplasia of adipose tissue is critical for the development of obesity, but molecular mechanisms governing normal or pathological recruitment of new adipocytes remain unclear. The extracellular signal–regulated kinase (ERK) pathway plays a pivotal role in many essential cellular functions, such as proliferation and differentiation. Using ERK1^−/− mice, we investigated the role of this isoform in adipose tissue development. Mice lacking ERK1 have decreased adiposity and fewer adipocytes than wild-type animals. Furthermore, ERK1^−/− mice challenged with high-fat diet are resistant to obesity, are protected from insulin resistance, and have a higher postprandial metabolic rate. To get insights into cellular mechanisms implicated in reduced adiposity in ERK1^−/− animals, we analyzed adipocyte differentiation in ERK1^−/− cells. Compared with wild-type control cells, mouse embryo fibroblasts and cultures of adult preadipocytes isolated from ERK1^−/− adult animals exhibit impaired adipogenesis. An inhibitor of the ERK pathway does not affect the residual adipogenesis of the ERK1^−/− cells, suggesting that ERK2 is not implicated in adipocyte differentiation. Our results clearly link ERK1 to the regulation of adipocyte differentiation, adiposity, and high-fat diet–induced obesity. This suggests that a therapeutic approach of obesity targeting specifically the ERK1 isoform and not ERK2 would be of particular interest.