Genetic variation on the Y chromosome is one of the best-documented causes of male infertility, but the genes responsible have still not been identified. This review discusses how an evolutionary perspective may help with interpretation of the data available and suggest novel approaches to identify key genes. Com- parison with the chimpanzee Y chromosome indicates that USP9Y is dispens- able in apes, but that multiple copies of TSPY1 may have an important role. Comparisons between infertile and control groups in search of genetic suscepti- bility factors are more complex for the Y chromosome than for the rest of the genome because of population stratification and require unusual levels of con- firmation. But the extreme population stratification exhibited by the Y also allows populations particularly suitable for some studies to be identified, such as the partial AZFc deletions common in Northern European populations where further dissection of this complex structural region would be facilitated.