Indigenous Australians have been particularly affected by type 2 diabetes mellitus due to their genetic susceptibility and a range of environmental risk factors. Recent genetic studies link predisposition to some diseases, including diabetes, to archaic humans, such as Neanderthals and Denisovans, suggesting persistence of ancient alleles in the genomes of modern humans. In this review we discuss the evolutionary role of the negative genetic selection associated with an adopted Western lifestyle as well as DNA variants influencing predisposition to obesity and diabetes in the Australian Indigenous population. We review the contribution of the ancient gene/pathways to the modern human phenotypes including the Neanderthal haplotype-tagging SNPs in NTRK2 gene, which may continue to play a role in obesity in Indigenous Australians.