Considerable attention has been focused on how the APOL1/MYH9 locus determines susceptibility to focal segmental glomerulosclerosis, including HIV-associated nephropathy (HIVAN). Atta and colleagues found that homozygosity for APOL1 risk alleles was associated with many, but not all, HIVAN cases, and that APOL1 variation failed to predict characteristics of disease. Their work gives important impetus to identify other genetic and environmental factors that may provide a 'second hit' linking HIV infection to HIVAN.