Of the various types of DNA damage that can occur within the mammalian cell, the DNA double strand break (DSB) is perhaps the most dangerous. DSBs are typically induced by intrinsic sources such as the by products of cellular metabolism or by extrinsic sources such as X-rays or gamma-rays and chemotherapeutic drugs. It is becoming increasing clear that an inability to respond properly to DSBs will lead to genomic instability and promote carcinogenesis. The mammalian cell, therefore, has in place several mechanisms that can respond rapidly to DSBs. In this review, we focus on the role of one such mechanism, the non-homologous end joining (NHEJ) pathway of DSB repair, in maintaining genome integrity and preventing carcinogenesis.