The cell cycle controls the competition between C-NHEJ and resection-dependent repair pathways. Extensive end resection is stimulated in the S/G2 phase of the cell cycle in a manner that depends on CDK activity, which mediates phosphorylation of multiple substrates, such as components of the MRN complex and CtIP. In the G1 phase of the cell cycle, 53BP1 and Rif1 proteins localize to DSBs, inhibit BRCA1 recruitment, block DNA end resection thus promoting C-NHEJ. In the S and G2 phases of the cell cycle, the ATM kinase, which phosphorylates members of the MRN complex, BRCA1, CtIP, or BLM favors the three resection-dependent DSB repair pathways (HR, alt-EJ, or SSA). However, recent evidence also suggests that alt-EJ could occur in G1 [105]. Abbreviations: ATM, Ataxia Telangiectasia Mutated; CDK, cyclin-dependent kinase; DSBs, double-strand breaks; MRN, MRE11, RAD50, and NBS1; C-NHEJ, classical nonhomologous end joining; HR, homologous recombination; alt-EJ, alternative end joining; SSA, single-strand annealing.