Traditional risk factors do not account for increased cardiovascular disease in patients with chronic kidney disease (CKD), particularly individuals whose CKD has progressed to end-stage kidney disease requiring dialysis. CKD patients on dialysis show little to no cardiovascular benefits from lipid-lowering therapy and thus have an exaggerated residual cardiovascular risk. High density lipoprotein (HDL) quantity and functionality may explain some of the residual risk. CKD affects the composition and disrupts the functionality of HDL, including cholesterol acceptor function and inflammatory effects. Notably, although these HDL abnormalities prevail in CKD, they do not track together and thereby support the idea of separate and distinct mechanistic pathways for each critical function of HDL. Targeting individual perturbations in HDL function represents a novel approach to therapy in this population.