A systematic approach to the evaluation and characterization of treatment resistance in schizophrenia has become increasingly important since the introduction of the second-generation antipsychotics. The need for accurate evaluation will increase further as other new antipsychotic medications are developed. Patients with schizophrenia may manifest poor response to therapy because of intolerance to medication, poor adherence, inappropriate dosing, as well as true resistance of their illness to antipsychotic drug therapy. Criteria for treatment-resistance are presented to help in standardizing treatment and clinical trials. As clinicians face the decision of when to change or augment antipsychotic medications, a clear understanding of the appropriate length of a treatment trial and which target symptoms respond to antipsychotic therapy is critical for maximizing response in patients with treatment-resistant schizophrenia.