Apolipoprotein L1 (APOL1) is associated with increased incidence of chronic kidney disease (CKD) and end-stage renal disease, and with faster progression of CKD, in African Americans. APOL1 is expressed in intra- and extrarenal vascular tissue, making it a candidate to explain the increased incidence of cardiovascular disease in CKD. This Commentary discusses the disparate results from three studies showing that APOL1 renal risk genotypes are either harmful, neutral, or protective in the context of cardiovascular disease.