The evolution and improvement of immunosuppressive regimens in organ transplantation has led to improved patient and graft survival rates and reduced rates of acute rejection; however, these improvements may be leading to greater incidence of severe adverse events, such as infections, nephrotoxicity and diabetes. The evaluation of new regimens therefore requires detailed risk/benefit analyses and consideration of more relevant clinical outcomes. Additionally, there is tremendous variation in treatment combinations, doses, and concentration monitoring leading to challenges in designing and interpreting active-controlled clinical trials. Lastly, recent failures of confirmatory clinical trials have raised concern regarding the absence of sufficient phase II dose-finding. This talk will outline the critical issues surrounding clinical trials in organ transplantation with case examples.