The estimated percentage of persons with schizophrenia who are overweight is higher than the percentage of persons in the general population who are overweight. The increased mortality rate for persons with schizophrenia is largely due to obesity-related diseases. The atypical antipsychotics offer an improved therapeutic index when compared with the conventional agents, but may impart serious adverse events such as weight gain. This brief review is intended to provide the practicing clinician with an update of disparate research paradigms under investigation in an attempt to delineate the biological mechanisms that presage weight gain. Research success in this area may invite novel prevention strategies and hint at potential mechanisms of antipsychotic drug action.