Although large-scale structural variations and chromosomal translocations are common in many cancers, relatively little is known about molecular mechanisms that cause genome rearrangements. Translocations are thought to begin with a double-stranded break in two chromosomes. In two recent papers, Chiarle et al. and Klein et al. investigated what genomic translocations occur when an experimentally introduced double-stranded break is repaired by an immune cell. Both groups studied B lymphocytes and used a specific meganuclease to cause breaks in either the c-myc gene or the IgH locus (an IgH/c-myc translocation is involved in the genesis of many B-cell lymphomas). DNA libraries enriched for rearrangements were sequenced by high-throughput sequencing. The authors found a wide spectrum of translocations involving all chromosomes. The analysis of hundreds of thousands of individual events in wild-type primary cells showed that the translocation sites are not randomly distributed in the genome, but that a small number of hotspots exist. The majority of translocations are within active genes, mostly around the transcriptional start site. The activation-induced cytidine deaminase (AID), a protein involved in IgH class switch recombination and somatic hypermutation, also contributes to the genesis of translocations by initiating double-stranded DNA breaks, as many hotspots observed in wild-type cells disappear when AID knockout cells are analyzed. (Cell 147, 95–106, 2011; Cell 147, 107–119, 2011)