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PURPOSE OF REVIEW: Cholesterol metabolism is increasingly recognized in inflammatory diseases including transplantation. This review discusses the mechanistic underpinnings that tie macrophage cholesterol efflux capacity of high-density lipoprotein to chronic rejection in transplanted patients. RECENT FINDINGS: Animal studies suggest that administration of apolipoprotein A-I, the main protein constituent of high-density lipoprotein, can prevent transplant atherosclerosis. apoA-I administration increases cholesterol efflux capacity of high-density lipoprotein. In patients with cardiac allograft vasculopathy, decreased cholesterol efflux capacity has been associated with poorer survival. In addition, reduced cholesterol efflux capacity in recipients, pre-transplant, has been associated with development of cardiac allograft vasculopathy and renal allograft survival. SUMMARY: These recent findings raise the hypothesis that increasing cholesterol efflux may prevent chronic rejection and improve allograft survival after transplant. Reconstituted high-density lipoprotein significantly increases cholesterol efflux capacity and is currently in clinical development for traditional atherosclerosis. Clinical trials of reconstituted high-density lipoprotein administration in transplantation should be performed.