The finding of acquired chromosomal translocations that are consistently associated with specific tumour types supports the premise of lineage-specific mechanisms of tumorigenesis. We review the evidence indicating that the specificity of these translocations and the corresponding gene fusions is related to biological constraints at the level of recombination, expression, and protein function. A dynamic relationship between the gene fusion and the cellular environment is proposed in which the environment influences the selection of oncogenic fusions and the oncogenic fusion in turn influences the cellular environment.