The prevalence of overweight and obesity is higher in people with mental illness than in the general population. Body weight is tightly regulated by a complex system involving the cortex and limbic system, the hypothalamus and the gastrointestinal tract. While there are justifiable concerns about the weight gain associated with antipsychotic medication, it is too simplistic to ascribe all obesity in people with serious mental illness (SMI) to their drug treatment. The development of obesity in SMI results from the complex interaction of the genotype and environment of the person with mental illness, the mental illness itself and antipsychotic medication. There are dysfunctional reward mechanisms in SMI that may contribute to poor food choices and overeating. While it is clear that antipsychotics have profound effects to stimulate appetite, no one receptor interaction provides an adequate explanation for this effect, and many mechanisms are likely to be involved. The complexity of the system regulating body weight allows us to start to understand why some individuals appear much more prone to weight gain and obesity than others.