Aberrant fusions between heterologous chromosomes are among the most prevalent cytogenetic abnormalities found in cancer cells. Oncogenic chromosomal translocations provide cells with a proliferative or survival advantage. They may either initiate transformation or be acquired secondarily as a result of genomic instability. Here, we highlight recent advances toward understanding the origin of chromosomal translocations in incipient lymphoid cancers and how tumor-suppressive pathways normally limit the frequency of these aberrant recombination events. Deciphering the mechanisms that mediate chromosomal fusions will open new avenues for developing therapeutic strategies aimed at eliminating lesions that lead to the initiation, maintenance, and progression of cancer.