In the past decades, the incidence of cancer keeps its rapid increasing step all over the world and cancer is always an important threat to public health. It is believed that cancer is resulted from a series of genetic alterations leading to 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, predicator of drug and therapy responses, or indeed as target for novel gene therapy is recently patented and very promising. In this review, we have summarized the studies investigating the association between XRCC4, one of the NHEJ genes, and the susceptibility to multiple cancers, and discussed its role in carcinogenesis and application in anticancer drug discovery.