Over the past few decades, the incidence of cancer has rapidly increased all over the world and cancer remains a major threat to public health. It is believed that cancer results from a series of genetic alterations that lead to the progressive disorder of the normal mechanisms controlling cell proliferation, differentiation, death and/or genomic stability. The response of the cell to genetic injury and its ability to maintain genomic stability by means of a variety of DNA repair mechanisms are therefore essential in preventing tumor initiation and progression. From the same viewpoint, the relative role of DNA repair as a biomarker for prognosis, predictor of drug and therapy responses or indeed as a target for novel gene therapy, is very promising. In this article, we have summarized the studies investigating the association between the XRCC5/XRCC6 dimer and the susceptibility to multiple cancers and discuss its role in carcinogenesis and its potential application to anticancer drug discovery.