Our genome integrity is under attack every day by a variety of exogenous and endogenous sources . Multiple cellular DNA repair mechanisms exist to remove damaged regions of chromosomes . Besides DNA repair, the genetic information can also be protected by other biological processes such as cell cycle checkpoints and apoptosis . Depending on the damage sources, DNA encounters diverse types of lesions such as base modifications, single strand breaks (SSB), or double strand breaks (DSB) that perturb the primary structure of DNA . Among DNA damage, DSBs are the most deleterious DNA lesions in light of their high levels of propensity to evoke genomic instability and cancer . Homologous recombination (HR) and nonhomologous end joining (NHEJ) are the two major pathways responsible for the repair of DSBs in higher eukaryotes. Mutations in DSB repair proteins are frequently associated with an increased risk of cancer . Besides, hyperactivation of DSB repair genes is one of the reasons for radio- and chemoresistance . In addition to understanding the critical roles of protein-coding driver genes in DNA damage response (DDR), efforts have been focused on identifying long non-coding RNAs (lncRNAs) that are largely transcribed from cancer risk loci and investigating how they can be potential biomarkers during anti-cancer therapy . LncRNAs are deregulated in cancer tissues and their altered expressions are most likely caused by copy number variations or single nucleotide polymorphisms (SNPs) [8, 9]. Given that the majority of lncRNAs have no assigned function, they are likely to provide an abundance of opportunities for revealing novel pathways that could conceivably be targeted for cancer therapy. Throughout this review, we guide readers to the most recent studies that describe in great detail unique characteristics of lncRNAs during DSB repair pathways. We first define the link between DSB and tumorigenesis and then describe noteworthy anti-cancer regimens using DSB repair. Finally, we focus on reviewing the functional roles of lncRNAs in DDR.