Human foragers avoid noncommunicable diseases that are leading causes of mortality, partly because physically active lifestyles promote healthy aging. High activity levels also promote tissue damage accumulation from wear-and-tear, increase risk of injury and disability which compromise productivity, and reduce energetic investments in somatic maintenance given constrained energy expenditure. Constraints intensify when nutrient supply is limited and surplus energy is directed toward pathogen defense and reproduction, as occurred throughout hominin evolution. This paper reviews evidence linking exposomes to musculoskeletal health in subsistence populations, focusing on effects of physical activity, pathogens, diet, and reproduction. Chronic musculoskeletal conditions are common for humans and possibly prehistoric hominins but rarer in quadrupedal apes. We propose that transition to bipedalism ~6 to 8 million years ago constituted an early “mismatch scenario," increasing hominin susceptibility to musculoskeletal conditions vis-à-vis quadrupedal apes due to changes in mechanical loading environments. Mismatched musculoskeletal traits were not targets of selection because of trade-offs favoring bipedal extractive foraging and higher fertility.