• The landscape of tuberculosis (TB) treatment has evolved considerably over the last 10 years, necessitating careful consideration of various trial design aspects to ensure that TB phase III trials are still impactful at trial completion, often more than 4–5 years after initial design. • The choice of control is guided by the specific trial objectives, weighing the relative merits of internal validity and external generalizability alongside randomization in making the correct inference. A particular challenge occurs when international or national guidelines change during the trial. • Improved execution and relevance of noninferiority trials for TB require greater emphasis on study quality, especially maximizing treatment adherence and minimizing missing outcome data; preferred use of intention-to-treat rather than per-protocol analyses; more careful justification of the margin of noninferiority; and consideration of recent innovations such as a Bayesian approach to noninferiority. • Many adaptive trial designs are well suited to optimization of TB treatment. A thorough understanding of type I error rates and biases in treatment effect estimates is critical for regulatory approval and consideration in establishing World Health Organization (WHO) guidelines. • Treatment stratification is an area of limited experience for TB trials, and trialists must learn from well-established methodology in other disease areas. • Explanatory trials are important for evaluating the efficacy of an intervention under close to ideal conditions. However, no single trial can address all relevant questions about a given therapeutic intervention at one time, and pragmatic trials will be essential for public health and policy decision-making purposes. • TB treatment trials today should favor bold and creative approaches that can produce high-quality evidence for effective, patient-centered care made accessible to all 10 million new TB patients, including the half-million with drug-resistant TB (DR-TB), each year.