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Modern humans exhibit marked musculoskeletal changes when compared to those of our African ape relatives, such as chimpanzees, bonobos, and gorillas. These changes reflect adaptive shifts during hominin evolution in spine, pelvis, knee, and foot morphology toward obligate bipedalism, shoulder, elbow, and hand morphology for propulsive throwing and precision object manipulation, and brain size expansion and craniofacial morphology for enhanced cognition related to complex culture and language. The molecular basis for these traits remains unknown, in part owing to the experimental difficulties in connecting DNA base-pairs to phenotypes. Here, we discuss recent methodological advances in the life sciences that help to connect genotype to phenotype and pave the way for understanding the molecular basis for human skeletal evolution. In this context, we also discuss the importance of recent findings in how adaptive evolution shapes modern disease risk.