DNA double-strand breaks (DSBs) occur commonly in the all living and in cycling cells. They constitute one of the most severe form of DNA damage, because they affect both strand of DNA. DSBs result in cell death or a genetic alterations including deletion, loss of heterozygosity, translocation, and chromosome loss. DSBs arise from endogenous sources like metabolic products and reactive oxygen, and also exogenous factors like ionizing radiation. Defective DNA DSBs can lead to toxicity and large scale sequence rearrangement that can cause cancer and promote premature aging. There are two major pathways for their repair: homologous recombination(HR) and non-homologous end-joining(NHEJ). The HR pathway is a known "error-free" repair mechanism, in which a homologous sister chromatid serves as a template. NHEJ, on the other hand, is a "error-prone" pathway, in which the two termini of the broken DNA molecule are used to form compatible ends that are directly ligated. This review aims to provide a fundamental understanding of how HR and NHEJ pathways operate, cause genome instability, and what kind of genes during the pathways are associated with head and neck cancer.