The generation of DNA double strand breaks (DSBs) is considered a lethal insult to the integrity of chromosomes. If not repaired, DSBs can lead to daunting consequences such as chromosome fragmentation, deletion, or rearrangement. While a plethora of DSB repair activities are available to cells, inappropriate execution of DSB repair pathways can also be a source for chromosome aberrations. It is proposed that inaccurate joining of DSBs is involved in the generation of the extraordinarily clustered chromosome rearrangements, i.e. chromothripsis, in primary tumors and cancer cell lines. Cells are commonly equipped with at least two major DSB repair pathways – homologous recombination (HR) and non-homologous end joining (NHEJ). These two repair pathways are necessitated for the maintenance of genome stability. Although physiologic DSBs are essential for meiosis and immunoglobulin gene rearrangements, the majority of them are pathologic. It is estimated that 10 DSBs can occur in an average human cell per day. Generally, two-ended DSBs are preferred substrates for NHEJ, and the repair of one-ended DSBs can only be carried out by HR.