Investigations of the legacy of natural selection in the human genome have proved particularly informative, pinpointing functionally important regions that have participated in our genetic adaptation to the environment. Furthermore, genetic dissection of the intensity and type of selection acting on human genes can be used to predict involvement in different forms and severities of human diseases. We review here the progress made in population genetics studies toward understanding the effects of selection, in its different forms and intensities, on human genome diversity. We discuss some outstanding, robust examples of genes and biological functions subject to strong dietary, climatic and pathogen selection pressures. We also explore the possible relationship between cancer and natural selection, a topic that has been largely neglected because cancer is generally seen as a late-onset disease. Finally, we discuss how the present-day incidence of some diseases of modern societies may represent a by-product of past adaptation to other selective forces and changes in lifestyle. This perspective thus illustrates the value of adopting a population genetics approach in delineating the biological mechanisms that have played a major evolutionary role in the way humans have genetically adapted to different environments and lifestyles over time.