Genetic variants in the APOL1 gene, found only in individuals of recent African ancestry, greatly increase risk of multiple types of kidney disease. These APOL1 kidney risk alleles are a rare example of genetic variants that are common but also have a powerful effect on disease susceptibility. These alleles rose to high frequency in sub-Saharan Africa because they conferred protection against pathogenic trypanosomes that cause African sleeping sickness. We consider the genetic evidence supporting the association between APOL1 and kidney disease across the range of clinical phenotypes in the APOL1 nephropathy spectrum. We then explore the origins of the APOL1 risk variants and evolutionary struggle between humans and trypanosomes at both the molecular and population genetic level. Finally, we survey the rapidly growing literature investigating APOL1 biology as elucidated from experiments in cell-based systems, cell-free systems, mouse and lower organism models of disease, and through illuminating natural experiments in humans.