Metabolic syndrome is a complex pathology characterized by imbalances in lipid and glucose metabolism and weight gain, and consequently by an increase in the incidence of type II diabetes and cardiovascular disease. Metabolic syndrome is rapidly becoming one of the most important side effects of treatment with modern “atypical” antipsychotic agents, probably due to their specific mechanisms of action. Although the most recent members of this class (aripiprazole, asenapine, ziprasidone) seem to produce a reduce incidence of metabolic syndrome, the problem is far from being resolved. In this chapter, the three most important classical neuroleptics (chlorpromazine, haloperidol and loxapine) and the most important atypical antipsychotics will be individually analyzed in relation to their propensity to cause metabolic syndrome. The most reliable, current data will be presented, also in the perspective of possible interventions to mitigate metabolic imbalances, comparative studies, switching studies and augmentation strategies. An important strategy for metabolic syndrome prevention could also be the performing of an accurate therapeutic drug monitoring (TDM). Thus, an up-to-date overview will also be presented of recent and significant analytical methods for the determination of the drugs of interest and their main metabolites in human biological fluids.