Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) is a complex multisystem illness that lacks effective therapy and a biomedical understanding of its causes. Despite a prevalence of approximately 0.2-0.4% and its high public health burden, and evidence that it has a heritable component, ME/CFS has not yet benefited from the advances in technology and analytical tools that have improved our understanding of many other complex diseases. Here we critically review existing evidence that genetic factors alter ME/CFS risk before concluding that most ME/CFS candidate gene associations are not replicated by the larger CFS cohort within UK Biobank. Multiple genome-wide association studies of this cohort also have not yielded consistently significant associations. Ahead of upcoming larger genome-wide association studies we discuss how these could generate new lines of enquiry into the DNA variants, genes and cell-types that are causally involved in ME/CFS disease.