The genome is constantly subjected to spontaneous damage from exogenous and endogenous damaging agents. Of all DNA lesions, DNA double strand breaks (DSB) are the most genotoxic as they may lead to loss of large parts of the chromosome, potentiate chromosomal rearrangements, and ultimately result in the development of cancer. The eukaryotic Mrell/RadSO/Nbsl (MRN) complex is a key player in the reversal of DSBs and has been linked to roles in DSB detection, checkpoint signalling, homologous recombination and non-homologous end joining (NHEJ). Hypomorphic mutations within MRN components confer genome instability and susceptibility to cancer in humans. Using a Xenopus egg extract system I have demonstrated a role for the MRN complex in an alternative DNA end joining pathway, distinct from classical NHEJ, termed microhomology-mediated end joining.