Africa, specifically Sub-Saharan Africa, has played a central role in modern human history, from our earliest ancestors to shaping evolutionary trajectories. While the ‘Out-of-Africa’ migration event gave rise to genetically limited founder derived non-African populations, within Africa populations represent the richness of human genetic diversity with direct clinical implications. Here, the Ancestry and Health Genomics laboratory has been interrogating African genomes, generating a more comprehensive landscape of genetic variation. Mapping Southern African Khoe-San and highly diverse Bantu and Nilotic derived human lineages - the team is demystifying the broadly used ‘African’ identifier into unique population substructures and phylogenies, including early divergence and once global predominance. Further elaborating on the important role that Southern Africa has played in modern human prehistory, the team has created a catalogue of early derived human variance, including the identification of over 1.3 million new small variants and almost 8,000 new structural variants. Presenting untapped potential to understand disease globally, in turn the team has been highlighting the inequity in benefits for Africans with respect to precision medicine. These range from non-African biases in genetic databases, variant detection assays and gene panels, to computational prediction tools, pangenomes and detection workflows, and ultimately new understanding with regards to disease presentation and outcomes.