The aim of this review is to analyse and summarise the literature data about the incidence of weight gain in patients exposed to atypical antipsychotics during long-term (>or=1 year) treatment regimens. Despite the clinical relevance of the topic, the vast majority of reviewed studies showed methodological limitations. Some trials had retrospective analysis, and concomitant medications also associated with an increased risk of weight gain, such as antidepressants and mood stabilisers, were often prescribed. Results were obtained from clinical trials conducted using flexible dosages; thus, the relationship between dosage and weight change was not explored adequately. Also, in a large number of studies, the average antipsychotic daily dose was lower than the usual dosage in clinical practice. Moreover, weight gain was evaluated by different measures, such as mean weight gain in the enrolled population, percentage of patients who gained >7% of basal weight or body mass index (BMI) variations from baseline. In short-term studies, a definite rank order of weight-gain potential among atypical antipsychotics has been demonstrated: clozapine is related to the highest risk of weight gain, followed in decreasing order of magnitude by olanzapine, quetiapine, risperidone, amisulpride, aripiprazole and ziprasidone. However, in long-term studies, except for clozapine at one end of the scale and ziprasidone at the other, the differences in weight-gain liability showed by the other atypical antipsychotics became less intense. Differences between short-term and long-term treatment could be due to a complex overlapping of different factors, both drug-specific (relative receptorial affinity; timing of weight change plateau; and drug-specific/dose-dependent weight gain), and patient-specific (genetic vulnerability; sex; age; BMI; weight before starting antipsychotic treatment; type of psychiatric disorder; and individual lifestyle). There is an urgent need for well designed, randomised controlled trials to assess firmly both the differential effects of atypical antipsychotics on weight and the role of other factors in contributing to iatrogenic unwanted weight changes. Meanwhile, the well known benefits shown by some atypical antipsychotics in reducing akathisia and other extrapyramidal adverse effects and improving cognition should be carefully balanced with the problems of weight gain, other metabolic complications and higher health care costs.