Understanding the influence of genetics on human disease is among the primary goals for biology and medicine. To this end, the direct study of natural human genetic variation has provided valuable insights into human physiology and disease as well as into the origins and migrations of humans. In this review, we discuss the foundations of population genetics, which provide a crucial context to the study of human genes and traits. In particular, genome-wide association studies and similar methods have revealed thousands of genetic loci associated with diseases and traits, providing invaluable information into the biology of these traits. Simultaneously, as the study of rare genetic variation has expanded, so-called human knockouts have elucidated the function of human genes and the therapeutic potential of targeting them.