The discovery of apolipoprotein L1 (APOL1) gene variants and its association with kidney disease in African‐Americans represent a significant breakthrough in understanding the genetic basis of ancestry‐based differences in a public health problem. The role these variants play in renal transplantation is still incompletely understood. This article reviews the epidemiologic data and current reports of APOL1 variant pathogenesis in transplantation. We examine existing data on outcomes in APOL1 high‐risk kidneys, high‐risk APOL1 recipients, live donors with high‐risk mutations and non–renal transplantation of high‐risk APOL1 organs. We discuss the rapidly evolving role and potential pros and cons of APOL1 genotyping of donors and recipients in transplantation. Finally, we highlight the ongoing nationwide National Institutes of Health‐sponsored “APOL1 Long‐term Kidney Transplantation Outcomes (APOLLO)” study, which will quantify outcomes and “second hits” in pertinent to APOL1 high‐risk variants in renal transplantation.