Chromosome translocations are catastrophic genomic events and often play key roles in tumorigenesis. Yet the biogenesis of chromosome translocations is remarkably poorly understood. Recent work has delineated several distinct mechanistic steps in the formation of translocations, and it has become apparent that non-random spatial genome organization, DNA repair pathways and chromatin features, including histone marks and the dynamic motion of broken chromatin, are critical for determining translocation frequency and partner selection.