Outcomes after lung transplantation remain disappointing because there is a high incidence of chronic lung allograft dysfunction (CLAD), which typically follows a progressive clinical course and often results in allograft failure and death. Chronic rejection is considered the predominant cause of CLAD. Thus, optimal immunosuppression has been viewed as having the potential to prevent CLAD and improve survival after lung transplantation. Numerous clinical trials have been conducted investigating the efficacy and safety of various immunosuppressive agents. Many studies have been small and single-center clinical trials but some have been international and multicenter trials enrolling more than 300 patients. This review focuses on clinical trials of immunosuppression conducted in lung transplantation and points out strengths and limitations of the various studies. Ultimately, the findings of these clinical trials explain the current state of practice in lung transplantation and identify gaps in knowledge that require additional study. Finally, there is an ongoing need for carefully designed and conducted clinical trials to improve clinical practice and outcomes after lung transplantation.