While differences in weight-gain potential exist, both between and within classes of psychiatry medications, most commonly used atypical antipsychotics, mood stabilizers, and antidepressants result in some degree of weight gain. This is not new information and it requires an understanding of the tolerability profiles of different treatments and their goodness of fit with specific patient phenotypes. However, this iatrogenic association represents only a piece of this obesity–mental illness dyad. The complex interplay between psychiatric illness and weight involves neurobiology, psychology, and sociological factors. Parsing the salient variables in people with mental illness is an urgent need insofar as mortality from physical health causes is the most common cause of premature mortality in people with chronic mental illness. Our review examines issues associated with common chronic mental illnesses that may underlie this association and warrant further study if we hope to clinically intervene to control this life-threatening comorbidity.