Many cancers exhibit chromosomal rearrangements. These rearrangements can be simple with a single balanced fusion preserving the proper complement of genetic information or they can be complex with one or more fusions that distort this balance. A range of technological advances has improved our ability to detect and understand these rearrangements leading to speculation of causal mechanisms including defective DNA double strand break (DSB) repair and faulty DNA replication. A better understanding of these potential cancer-causing mechanisms will lead to novel therapeutic regimes to fight cancer. This review describes the technological advances used to detect simple and complex chromosomal rearrangements, cancers that exhibit these rearrangements, potential mechanisms that rearrange chromosomes and intervention strategies designed to specifically attack fusion gene products and causal DNA repair/synthesis pathways.