Body weight is determined by the interaction of the genetic makeup of an individual and the environment in which that person is living. The control systems that regulate body weight are numerous and include signals from fat that travel to the hypothalamus where cognitive and internal signals are integrated. The integration of these signals involves a complex array of neuropeptides, neurotransmitters and structural circuits. These circuits regulate appetite, intake and energy expenditure. Recent studies demonstrate that the theory of a thrifty genotype is probably correct. Some people are more susceptible to our obesogenic environment than others. Some people are able to overwhelm their genetics by voluntarily increasing energy expenditure and decreasing food intake; a feat that is rarely accomplished and requires a Herculean effort. As we better understand the environmental, genetic, physiological, and behavioral aspects of obesity, we will undoubtedly develop better strategies and therapies for obesity.