The CATIE schizophrenia trial provided the opportunity to implement and evaluate innovative approaches to human subjects concerns. These concerns included their abilities to provide informed consent, the durability of such abilities, and the protections of human research subjects. This chapter describes the special human subjects procedures used in the trial and summarizes the research results. Through the MacArthur Competence Assessment Tool-Clinical Research (MacCAT-CR) was used to screen individuals who demonstrated adequate decision-making capacity and they were able to continue in the study. Subject advocate procedures were developed to help ensure objective consideration of a subject's interests. The primary goal of the subject advocate was to ensure that the interests of research participants with schizophrenia were protected in the context of a multi-phase clinical trial. Study participants with marginal capacity at the time of enrollment and with worsening psychopathology during the study were at risk of lost capacity.