The current human genome was moulded and refined through generations of time. We propose that the basic framework for physiologic gene regulation was selected during an era of obligatory physical activity, as the survival of our Late Palaeolithic (50 000–10 000 BC) ancestors depended on hunting and gathering. A sedentary lifestyle in such an environment probably meant elimination of that individual organism. The phenotype of the present day Homo sapiens genome is much different from that of our ancient ancestors, primarily as a consequence of expressing evolutionarily programmed Late Palaeolithic genes in an environment that is predominantly sedentary. In this sense, our current genome is maladapted, resulting in abnormal gene expression, which in turn frequently manifests itself as clinically overt disease. We speculate that some of these genes still play a role in survival by causing premature death from chronic diseases produced by physical inactivity. We also contend that the current scientific evidence supports the notion that disruptions in cellular homeostasis are diminished in magnitude in physically active individuals compared with sedentary individuals due to the natural selection of gene expression that supports the physically active lifestyle displayed by our ancestors. We speculate that genes evolved with the expectation of requiring a certain threshold of physical activity for normal physiologic gene expression, and thus habitual exercise in sedentary cultures restores perturbed homeostatic mechanisms towards the normal physiological range of the Palaeolithic Homo sapiens. This hypothesis allows us to ask the question of whether normal physiological values change as a result of becoming sedentary. In summary, in sedentary cultures, daily physical activity normalizes gene expression towards patterns established to maintain the survival in the Late Palaeolithic era.