Long-term administration of typical and atypical antipsychotic drugs (AP) induces excessive weight gain which afflicts up to 50% of patients, impairs health and interferes with treatment compliance. Basic and clinical research has shown that AP may affect body weight through diverse mechanisms. Increased appetite is probably related to the interaction of AP with neuronal receptors to dopamine, serotonin and histamine. Additional metabolic-endocrine disruption of weight regulation may be related to the effects of AP-induced hyperprolactinaemia on gonadal-adrenal steroids and insulin sensitivity. In humans, programmed physical activity, dietary restriction, anorectic agents, and drugs that counteract hyperprolactinaemia have been shown to be successful in a limited number of studies. Two novel strategies could expand the available therapeutic options. First, in preclinical experiments in female rats the estradiol antagonist/agonist drug tamoxifen or estradiol itself have been shown to completely prevent the obesity provoked by the AP sulpiride, and to induce an endocrine-metabolic milieu that seems to counteract AP-induced obesity. Secondly, it has also been shown that oral antihyperglycaemic agents such as metformin may decrease body weight and counteract insulin resistance and hyperinsulinaemia which is correlated with several metabolic abnormalities in obese subjects. Lastly, estradiol replacement, tamoxifen and/or antihyperglycaemic agents are not devoid of significant side-effects, and these drugs have not been tested in obese psychiatric patients. Therefore, further research is needed before their clinical use may be recommended.