This chapter describes the development of the study designed to assess the effectiveness of antipsychotic drugs for persons with chronic schizophrenia. The protocol was developed by a team of academic investigators through an inclusive, iterative, and systematic process. The Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) program was designed to address a discrepancy between research demonstrating the efficacy of antipsychotic drugs and disappointing findings regarding their effectiveness and the ostensible superiority of second-generation antipsychotic (SGA) medications relative to first-generation antipsychotic drugs (FGA) medications. Some of the key study design decisions made by the Schizophrenia Protocol Development Committee, with input from various stakeholder groups, and their rationales are reviewed in this chapter. The study design was that of a practical clinical trial intended to evaluate the effectiveness of treatments in everyday settings to generate results intended to inform clinicians, administrators, policy makers, and patients.