Huxley and Darwin were among the first to appreciate the close evolutionary relationship of humans and other African great apes but also to ponder what genetic changes might make us human. Initial comparisons of human and chimpanzee genes, however, showed little difference (>99% identical) despite the numerous adaptations that must have occurred on various ape lineages. Most comparative genetic studies over the last two decades have emphasized subtle regulatory differences as underlying most human-chimp differences. Recent studies of more complex regions of our genome have revealed hotspots of rapid and dramatic evolutionary change. Embedded within these regions are hundreds of new duplicate genes several of which appear to be important in unique human-specific neuroanatomical adaptations including the expansion of the neocortex and increase in synaptic connectivity. These same regions have increased ape susceptibility to neurodevelopmental disease (eg. autism, intellectual disability and epilepsy) suggesting that human-specific genes and increased disease burden are linked.