High levels of spontaneous physical activity in lean people, and the Non-Exercise Activity Thermogenesis (NEAT) derived from that activity, appears to protect them from obesity during caloric challenge while obesity in humans is characterized by dramatically reduced spontaneous physical activity. We have similarly demonstrated that obesity resistant rats have significantly greater spontaneous physical activity than obesity prone rats, and that spontaneous physical activity predicts body weight gain. Although the energetic cost of activity varies between types of activity and may be regulated, individual level of spontaneous physical activity is important in determining propensity for obesity. We review the current status of knowledge about the brain mechanisms involved in controlling the level of spontaneous physical activity, and the NEAT so generated. Focus is on potential neural mediators of spontaneous physical activity and NEAT, including orexin A (also known as hypocretin 1), agouti-related protein (AGRP), ghrelin and neuromedin U (NmU), in addition to brief mention of neuropeptide Y, corticotrophin releasing hormone, cholecystokinin, estrogen, leptin and dopamine effects on spontaneous physical activity. We further review evidence that strain differences in orexin stimulation pathways for spontaneous physical activity and NEAT appear to track with the body weight phenotype, thus providing a potential mechanistic explanation for reduced activity and weight gain.