High-coverage sequencing of 180 individuals from 12 African populations reveals millions of new functional variants. San and central African rainforest hunter-gatherers (RHG) ancestors split from other populations more than 200,000 years ago. San and RHG maintained large effective population sizes. Africa shows ancient population structure. Multiple introgressions occurred from ghost populations with highly diverged genetic lineages. Gene flow persisted between eastern and southern Khoesan hunter-gatherers until about 12,000 years ago. Local adaptation signatures appear for skin color, immune response, height, and metabolism. Lightly pigmented San carry a positively selected PDPK1 variant that regulates pigmentation via enhancer activity and gene expression in vitro.