Nonadherence of transplant recipients to prescribed medical regimens has been identified as a major cause of allograft failure. Although recent studies offer new insight into the clinical phenotypes of nonadherence, advances in defining risk factors and appropriate interventions have been limited because of variable definitions, inadequate clinical metrics, and the challenges associated with healthcare delivery. Significant nonadherence is estimated to occur in 22% of renal allograft recipients and may be a component of allograft loss in approximately 36% of patients. It is associated with increased incidence of rejection (acute and chronic) and, consequently, shortened renal allograft survival, requiring reinstitution of costly chronic renal replacement therapy with an incumbent effect on morbidity and mortality. The economic effect of nonadherence approaches similar magnitude. Identification of risk factors, coupled with measures that effectively address them, can have a positive effect at many levels - medically, socially, and economically. Further advances are likely to be dependent on improving interactions between patients and caregivers, broadening immunosuppressant availability, and newer therapeutics that move toward simpler regimens. Copyright © 2010 by the American Society of Nephrology.