One prerequisite for therapeutic effects of psychiatric drugs is the ability to pass the blood brain barrier. Hence, it is important to know the concentration of antipsychotic drugs in brain tissue. In general, determinations of lipophilic compounds from lipophilic matricies such as the brain are a challenge. Here we have adapted a plasma assay for antipsychotics for the target organ the brain. Using modified sample preparation and chromatographic strategies, the analytes were extracted from rat brain homogenate and analyzed by LC-MS/MS. The method used a Waters Atlantis dC-18 (30 mm x 2.1 mm i.d., 3 microm) column with a mobile phase of acetonitrile/5 mM ammonium formate (pH 6.1 adjusted with formic acid) and gradient elution. All analytes were detected in positive ion mode using multiple-reaction monitoring. The method was validated and the linearity, lower limit of quantitation, precision, accuracy, recoveries, specificity and stability were determined. This method was then successfully used to quantify the rat brain tissue concentration of the analytes after chronic treatment with these antipsychotic drugs.