Despite dramatic improvements in acute rejection rates and short-term allograft survival, long-term allograft survival remains unchanged in the modern era, largely due to chronic allograft injury, a progressive disease that is common across all solid organ transplantation but has no proven treatment. Studies of novel diagnostic and therapeutic strategies for chronic allograft injury have been relatively sparse, in part due to the time and expense required to conduct traditional long-term clinical studies of a variably progressive disease. In this article, we review the pathophysiology of chronic allograft injury, including recent insights into key mechanisms of the disease. We discuss the barriers to progress in chronic allograft injury research and present alternative approaches to study design that could accelerate improvements in diagnosis, prevention, or treatment of the disease. We integrate these approaches with emerging biomarkers and surrogate endpoints into a model clinical study of chronic renal allograft injury, providing a framework for modern study design in solid organ transplantation.