Obesity develops when there is an imbalance between energy intake and energy expenditure, which can vary daily within and among individuals. High levels of energy intake and low levels of energy expenditure contribute to obesity, both together and independently. Energy expenditure from exercise associated with formal programs is encouraged for health and weight loss, but most individuals get very little formal exercise. Nonexercise activity thermogenesis (NEAT) is the cumulative energy expended through all other activities of daily living. It is highly variable among individuals; it is controlled by the environment and, possibly, neurobiologically. Mounting evidence suggests that NEAT is critical in determining a person's susceptibility to body fat deposition and is a major factor in human obesity. Recent research supported by the Minnesota Partnership for Biotechnology and Medical Genomics, a state-sponsored collaborative effort of the University of Minnesota and Mayo Clinic, is helping to define the complex brain regulation of NEAT and its role in obesity. This article reviews the evidence for NEAT and the impact of NEAT on obesity.