The prevalence of depression (10%) and overweight (65%) indicates that there is a probability that they will co-occur, but are they functionally related? This report used the moderator/mediator distinction to approach this question. Moderators, such as severity of depression, severity of obesity, gender, socioeconomic status (SES), gene-by-environment interactions and childhood experiences, specify for whom and under what conditions effects of agents occur. Mediators, such as eating and physical activity, teasing, disordered eating and stress, identify why and how they exert these effects. Major depression among adolescents predicted a greater body mass index (BMI = kg/m(2)) in adult life than for persons who had not been depressed. Among women, obesity is related to major depression, and this relationship increases among those of high SES, while among men, there is an inverse relationship between depression and obesity, and there is no relationship with SES. A genetic susceptibility to both depression and obesity may be expressed by environmental influences. Adverse childhood experiences promote the development of both depression and obesity, and, presumably, their co-occurrence. As most knowledge about the relationship between these two factors results from research devoted to other topics, a systematic exploration of this relationship would help to elucidate causal mechanisms and opportunities for prevention and treatment.