Extended-release paliperidone is a new atypical antipsychotic chemically related to the well-known antipsychotic risperidone. It has been formulated in an osmotic controlled-release oral delivery system that minimizes peak-trough fluctuations and, by obviating dose-titration, allows once-daily dosing with a therapeutically active dose from the first day. Its pharmacokinetic profile is characterized by a mean time-to-peak plasma concentration of 24.1 hours and an elimination half-life of approximately 24 hours. A dose of 6 mg of paliperidone extended-release (ER) provides a mean striatal D2 receptor occupancy of 64%, approaching the accepted lower receptor occupancy threshold required for optimal antipsychotic activity without causing extrapyramidal symptoms. It undergoes minimal hepatic biotransformation and is mainly excreted unchanged in the urine with four metabolic products. Three pivotal randomized, double-blind, placebo-controlled, parallel-group six-week trials investigated the efficacy, safety and tolerability of paliperidone ER at doses of 3-15 mg/day. All doses produced a significant reduction in schizophrenia symptomatology, with an onset of effect as of day 4. Personal and social functioning also improved as measured by the Personal and Social Performance scale. A prevention of recurrence study showed that paliperidone ER effectively prolonged the time-to-recurrence versus placebo. Paliperidone ER was efficacious in young, elderly and recently diagnosed schizophrenia patients. Beneficial effects on sleep assessed objectively and subjectively with minimal daytime somnolence were demonstrated. Overall, it was well-tolerated and had placebo-like discontinuation rates for adverse events. There were some dose-related extrapyramidal symptoms, mostly mild to moderate in intensity and associated with minimal changes in the rating scales that assessed extrapyramidal symptom severity. Although prolactin elevation occurred with paliperidone ER, only few prolactin-related adverse events were reported. There were no signals for metabolic dysfunction in terms of glucose, insulin, lipid or triglyceride changes or any indicators of clinically relevant cardiac events. Body weight increased slightly, but the changes were acceptable in the context of the doses likely to be used clinically, and patients with higher initial body mass index gained less weight as has been reported for other antipsychotics.