Treatment resistance is considered a challenging problem of antipsychotic pharmacotherapy. In such cases, combination approaches are commonly used, for instance the add-on of aripiprazole to clozapine. This review aims at giving an overview of the present knowledge on this strategy. We performed a keyword-based screening of databases (including November 2007) and evaluated the data in a systematic manner. The courses of 94 patients were reported in 11 publications. At a mean dosage of 20.5 mg/day, aripiprazole achieved clinical improvement of psychotic symptoms and facilitated a dose reduction of clozapine from 476.7 to 425.1 mg/day. In parallel, clozapine serum levels decreased from 611 to 523 ng/ml. No pharmacokinetic interactions were reported, and clozapine-induced side effects ameliorated. However, single cases of extrapyramidal side effects occurred. The combination of clozapine and aripiprazole follows a neurobiological rationale and appears to be effective and tolerable. The results of placebo-controlled trials might allow further insight into the benefits and risks of this strategy.