Despite major advances in understanding the pathophysiology of antibody-mediated rejection (AMR); prevention, diagnosis and treatment remain unmet medical needs. It appears that early T cell-mediated rejection, de novo donor-specific antibody (dnDSA) formation and AMR result from patient or physician initiated suboptimal immunosuppression, and represent landmarks in an ongoing process rather than separate events. On April 12 and 13, 2017, the Food and Drug Administration sponsored a public workshop on AMR in kidney transplantation to discuss new advances, importance of immunosuppressive medication nonadherence in dnDSA formation, associations between AMR, cellular rejection, changes in glomerular filtration rate, and challenges of clinical trial design for the prevention and treatment of AMR. Key messages from the workshop are included in this summary. Distinction between type 1 (due to preexisting DSA) and type 2 (due to dnDSA) phenotypes of AMR needs to be considered in patient management and clinical trial design. Standardization and more widespread adoption of routine posttransplant DSA monitoring may permit timely diagnosis and understanding of the natural course of type 2 and chronic AMR. Clinical trial design, especially as related to type 2 and chronic AMR, has specific challenges, including the high prevalence of nonadherence in the population at risk, indolent nature of the process until the appearance of graft dysfunction, and the absence of accepted surrogate endpoints. Other challenges include sample size and study duration, which could be mitigated by enrichment strategies.