Obesity is a leading risk factor for a variety of metabolic diseases including cardiovascular disease, diabetes, and cancer. Although in its simplest terms, obesity may be thought of as a consequence of excessive caloric intake and sedentary lifestyle, it is also evident that individual propensity for weight gain can vary. The etiology of individual susceptibility to obesity seems to be complex - involving a combination of environmental-genetic interactions. Herein, we suggest that the mitochondrion plays a major role in influencing individual susceptibility to this disease via mitochondrial-nuclear interaction processes and that environmentally influenced selection events for mitochondrial function that conveyed increased reproductive and survival success during the global establishment of human populations during prehistoric times can influence individual susceptibility to weight gain and obesity. © 2013 Elsevier Inc. All rights reserved.