This chapter addresses the key elements of CNS trial management required to drive successful outcomes in a high-risk environment. It presents an analysis of 123 studies conducted globally in schizophrenia, bipolar disorder, major depressive disorder, and generalized anxiety disorder. When designing clinical development plans, guidance should be sought from the European Agency for the Evaluation of Medicines (EMEA) and the Federal Food and Drug Administration (FDA). Evidence-based planning, effective implementation, and risk management are key to the successful delivery of a clinical plan. Phase I trials in healthy volunteers are conducted in a minimum number of sites. Phase II trials and even more so Phase III programs require far more extensive planning and access to patients. Diagnosis being complex and co-morbidities frequent in psychiatry, trial management methodology should focus on patient eligibility. Investigators and site coordination staff should be trained on the diagnostic tools and protocol-specific inclusion and exclusion criteria.