Second-generation antipsychotics (SGA) are associated with weight gain and metabolic alterations including hyperglycemia, dyslipidemia, hypertension and metabolic syndrome. These metabolic side effects increase cardiovascular risk and are related to medication non-compliance. Patients without previous exposure to these or other antipsychotic drugs (naive patients) seem to be more prone to develop these metabolic abnormalities. The mechanisms behind weight gain can be an increase in food intake and/or a decrease in energy expenditure. This review comprehensively examines the current knowledge on the impact of these drugs on food intake and energy expenditure. The influence of these drugs on appetite and food intake (total caloric intake and food sources) is reviewed as well as the evidence of abnormal eating behaviors. The studies evaluating the effect on resting energy expenditure are critically examined, taking into account the influence of body composition and previous exposure to antipsychotics (naive vs non-naive patients). Finally, the influence of these drugs on physical activity is also discussed. The knowledge of the mechanisms of weight gain in patients starting these drugs may be useful to further prompt research in this field and ameliorate the metabolic side effects associated with these treatments.