Using an epidemiologic model of the interactions between environmental agents and human hosts to explain obesity, we explored food, medications, physical inactivity, toxins, and viruses as environmental agents that interact with a genetically programmed host to disturb energy balance and cause obesity. Large portion sizes, high fat intakes, easy access to calorically sweetened beverages, and lack of any need to be physically active all play a role in the toxic environment that leads to obesity. The genetic and physiologic responses of a host determine whether or not this toxic environment will produce obesity. Reversing the current trends of obesity requires a new look at the limits of the energy balance concept, and a better understanding of how environmental factors acutely and chronically change the responses of susceptible hosts.