Enzymatically mediated rearrangement of Ig and T-cell receptor genes is essential for generating the huge molecular repertoire of the mammalian immune system, but it also carries a danger for the organism in the form of high risk zones for illegitimate juxtaposition of DNA from other areas of the genome. Translocation-dependent activation of oncogenes, transcription factors or developmental genes can trigger the development of neoplasia in a lineage-specific fashion. These events are not sufficient for tumorigenesis, however, since some of the most prominent tumor-associated translocations, such as Ig/myc and Ig/bcl-2, have been detected in normal individuals who did not develop tumors. Tumor development must, therefore, require subsequent genetic changes. Among them, the increased expression of genes that protect against apoptosis or, alternatively, mutations that cripple apoptosis-activating genes play a prominent role. Some of the translocations associated with T-cell leukemia, myeloid leukemia, and a variety of sarcomas act by generating fusion proteins. The participating genes encode transcription factors and/or developmental regulators. Fusion protein-expressing cells may serve as targets for specific interference with abnormal signaling pathways or for targeted immune attack. Using PCR to detect cells carrying such translocations is useful for tumor diagnosis, prognosis, and choice of therapy.