Objective: Paliperidone palmitate is now available as a three-month depot injection. This paper will review the pharmacokinetics, pharmacodynamics, efficacy and tolerability, as well as practical issues and pitfalls for clinicians with this innovative treatment for schizophrenia. Conclusion: The three-month depot formulation of paliperidone for the treatment of schizophrenia is not a new compound. The nanocrystalline structure of the three-month formulation is larger and takes longer to disperse than the one-month formulation, hence its extended depot action. As expected, it is non-inferior to one-month depot paliperidone, and superior to placebo, for the treatment of schizophrenia. The side effect profile of three-month paliperidone is identical to the one-month formulation. The relapse rate on treatment is low, and the median time to relapse after ceasing the drug is 395 days. An understanding of half-life and kinetics is crucial for clinicians using this compound, and the loading strategy is important to ensure effectiveness. There are significant challenges: ensuring timely administration and switching a three-month depot treatment to another antipsychotic may be problematic. Paliperidone palmitate three-month depot injection represents an advance for both convenience and effectiveness in the long term psychopharmacological treatment of schizophrenia.