Despite variations across individuals and agents, antipsychotics are associated with clearly documented weight gain and adverse metabolic effects. Although increased appetite/caloric intake and various receptors, hormones and peptides have been implicated, biological mechanisms contributing to the increase in weight and glucose and lipid abnormalities with antipsychotics are largely unknown. This has hampered the creation of antipsychotics that are free of cardiometabolic effects, even in antipsychotic-naive/early-phase patients, as well as the development of strategies that can prevent or drastically diminish the adverse cardiometabolic effects. In general, three strategies can reduce the cardiometabolic risk of antipsychotics: switching to a less orexigenic/metabolically adverse antipsychotic; adjunctive behavioral treatments; and adjunctive pharmacologic interventions. However, each of these strategies has only been shown to be modestly effective. Among different behavioral interventions (N = 14, n = 746), group and individual treatment, dietary counseling and cognitive-behavioral therapy seem to be similarly effective. Among 15 different pharmacologic strategies (N = 35, n = 1629), only metformin, fenfluramine, sibutramine, topiramate and reboxetine were more effective than placebo, with the most evidence being available for metformin, and no head-to-head trials comparing individual pharmacologic interventions. However, even in the most successful trials the risk reduction was modest. Weight was not decreased to a pretreatment level, and despite superiority compared with placebo, weight gain still often occurred, particularly in antipsychotic-naive patients and when interventions were 'preventively' coinitiated with antipsychotics. Future research should focus on combining treatment modalities or agents and on exploring novel mechanism-based interventions.