Faithful genome transmission requires the cooperation of a network of pathways including cell cycle checkpoint, DNA replication, repair and recombination. The different DNA repair pathways must also be coordinated as function of the type of damage, the cell cycle and differentiation. DNA double-strand breaks (DSBs) are highly toxic lesions, which can be produced by physiological cell processes, such as meiosis or V(D)J recombination or by genotoxic stresses, such as ionizing radiation or replication inhibition. In mammalian cells, two major classes of processes can repair DSBs: non-homologous end-joining (NHEJ) or homologous recombination (HR). It has been proposed that the two processes can compete, via the binding to the broken DNA ends by the Ku80-Ku70 heterodimer (NHEJ) versus RAD52 protein (HR). Consistent with the competition for the DNA ends model, mammalian NHEJ defective cells show increased HR, induced by DSB generating treatment; this stimulation is specific to DSB since neither spontaneous nor UV-C-induced HR are stimulated. However the regulation could be more complex since different cell situations can affect the choice between NHEJ and HR, such as the stage of embryonic development, the persistence and / or accumulation of DSBs. The phase of the cell cycle has also been proposed to affect this channeling. In addition, despite the cell cycle regulation, the two processes can cooperate or act sequentially. After describing the molecular mechanisms of NHEJ and HR processes, their regulation is presented and discussed in this review. A model of regulation of DSB repair with respect to the cell cycle is proposed.