The treatment of mental illness presents an opportunity to examine the heterogeneity of treatment effects. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) schizophrenia trial was sponsored by the National Institute of Mental Health (NIMH) to evaluate the effectiveness of antipsychotic medications for schizophrenia in broad patient populations and in scenarios representative of standard clinical practice. Trial inclusion criteria were broad and exclusion criteria were minimal, allowing for a heterogeneous study population. The majority of patients in each phase 1 treatment group discontinued their randomly assigned treatment owing to inadequate efficacy, intolerable side effects, or other reasons. Phase 2 of CATIE featured 2 treatment pathways (efficacy and tolerability) with randomized follow-up medication based on the reason for discontinuation of the previous antipsychotic drug. Outcome differences between treatment groups and variable responses to medications across the study suggest why multiple medication trials are common and may be necessary in the treatment of schizophrenia. Collectively, the CATIE results highlight variable response in the treatment of schizophrenia and demonstrate the need for individualized therapy based on variations in drug efficacy and tolerability among patients.