The same story has been presented on teaching rounds for the past 20 years: “Mr B. is a 63-year-old who underwent cardiac transplant 6 years ago. He was transplanted for ischemic heart disease and his current comorbidities include hypertension, hyperlipidemia, diabetes and progressive renal insufficiency.” At this point the temptation is to initiate an erudite discussion outlining the incidence of post-transplant renal dysfunction and its impact on outcomes. The brave clinician will implicate the immunosuppressive drugs in the etiology of renal dysfunction and attempt to summarize a complex literature that highlights the pathophysiology of calcineurin inhibitor (CNI)-induced nephrotoxicity. After all, the drugs must play an important role in the etiology, because the patient did not have significant antecedent renal dysfunction. The wise clinician will broaden the discussion to include other potential causes of renal insufficiency ranging from common comorbidities to peri-operative ischemic insults. The honest clinician will simply note that we actually have an inadequate understanding of the complex interactions of underlying disease processes, clinical events and post-transplant therapeutics in the development of one of the most common and important complications after cardiac transplantation. In a recent analysis of 69,321 recipients of non-renal solid-organ transplantation, 16% of patients developed renal dysfunction within 3 years, and nearly 30% of these patients required dialysis or renal transplantation. 1 Further, incident renal failure was associated with a 4.5-fold increase in mortality. The registry of the International Society for Heart and Lung Transplantation demonstrated that significant renal functional impairment after cardiac transplantation occurs in 26% of recipients at 12 months and 30% at 5 years, and nearly 6.5% of the cardiac transplant patients require renal replacement therapy by 10 years. 2