Paliperidone, the major active metabolite of risperidone (9-hydroxyrisperidone), is a second-generation antipsychotic that was recently approved by the United States Food and Drug Administration for treatment of acute schizophrenia and for maintenance treatment of schizophrenia. We performed a literature search of PreMEDLINE, MEDLINE, and International Pharmaceutical Abstracts from 1966-October 2007 to review the available data on the pharmacology, pharmacokinetics, clinical evidence, and safety and tolerability profile of paliperidone extended-release (ER). Articles from randomized controlled trials, abstracts, and posters presented at national scientific meetings were included in this review. Paliperidone ER has been shown to be significantly more effective in improving schizophrenic symptoms according to the Positive and Negative Symptom Scale (PANSS), Clinical Global Impressions-Severity Scale, and Personal and Social Performance Scale compared with placebo (p<0.05). In addition, limited evidence suggests similar efficacy between paliperidone ER 6-12 mg/day and risperidone 4-6 mg/day. A 2-week, double-blind comparison with quetiapine demonstrated that paliperidone ER was significantly better than quetiapine in improving PANSS scores (p<0.001). Paliperidone ER appears to be well tolerated at the recommended starting dosage of 6 mg/day. The most commonly reported adverse effect was dose-related extrapyramidal symptoms. Weight gain and metabolic disturbances were minimal. The cost of paliperidone ER appears to be slightly higher than that of other second-generation antipsychotics. Paliperidone ER tablets may be a safe and effective treatment option for acute schizophrenia and maintenance treatment of schizophrenia compared with placebo. Because well-designed comparative data are lacking, an additional benefit over other antipsychotics is yet to be determined.