What can clinicians take away from this rather confusing literature? Clearly monotherapy, when tolerated and effective, is optimal. When patients fail to respond to an adequate dose of an antipsychotic, clozapine is the only option with established efficacy. However, relatively few patients remain on a single antipsychotic for long (12), and adherence is often poor even when patients choose to remain on monotherapy. In other words, treating people with schizophrenia may require trials of several antipsychotics in order to find one that is well-tolerated at an effective dose. In some patients, combination treatment may be preferred after all other reasonable options have failed. In such patients, combination treatment using the lowest possible dose of each drug should be evaluated in a systematic, time-limited trial, and the evidence for benefit should be clear and well-documented if the combination is to be continued. As always, clinician judgment combined with patient preference must take over when treatment algorithms fall short.