Continued growth in the field of adult congenital heart disease has given rise to a critical mass of patients, investigators and resources dedicated to advancing knowledge through research. Impressive gains over the past decade have largely been driven by successful observational studies. Despite the privileged role of clinical trials in the hierarchy of evidence-based medicine, few such studies have thus far been conducted in adult congenital heart disease. Obstacles and challenges particular to clinical trials in adult congenital heart disease are addressed in this review. In looking ahead, examples of creative methodological solutions to maximizing the efficiency of clinical trials for rare diseases are discussed, including Bayesian analyses, outcome-adaptive randomization and internal pilot studies.