Pain is the leading cause of disability worldwide, imposing an enormous burden on personal health and society. Pain is a multifactorial and multidimensional problem. Currently, there is (some) evidence that genetic factors could partially explain individual susceptibility to pain and interpersonal differences in pain treatment response. To better understand the underlying genetic mechanisms of pain, we systematically reviewed and summarized genome-wide association studies (GWASes) investigating the associations between genetic variants and pain/pain-related phenotypes in humans. We reviewed 57 full-text articles and identified 30 loci reported in more than 1 study. To check whether genes described in this review are associated with (other) pain phenotypes, we searched 2 pain genetic databases, Human Pain Genetics Database and Mouse Pain Genetics Database. Six GWAS-identified genes/loci were also reported in those databases, mainly involved in neurological functions and inflammation. These findings demonstrate an important contribution of genetic factors to the risk of pain and pain-related phenotypes. However, replication studies with consistent phenotype definitions and sufficient statistical power are required to validate these pain-associated genes further. Our review also highlights the need for bioinformatic tools to elucidate the function of identified genes/loci. We believe that a better understanding of the genetic background of pain will shed light on the underlying biological mechanisms of pain and benefit patients by improving the clinical management of pain. Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Association for the Study of Pain.