Publisher Summary This chapter provides an insight into the molecular events occurring as a consequence of the first translocation that is specifically associated with one type of leukemia—the Philadelphia chromosome translocation. A hybrid gene is generated by the translocation, consisting of 5’ regulatory, promoter, and exon sequences of the breakpoint cluster region (BCR) gene on chromosome 22 fused to 3´ exons and polyadenylation/ termination sequences of the ABL oncogene originating from chromosome 9. Therefore, it is likely that such a hybrid gene will be regulated by an as-yet-unidentified transcriptional regulatory signals directed at the normal BCR gene. The attachment of a BCR moiety to the ABL protein has resulted in increased tyrosine kinase. In analogy to this increased activity and the transforming potential of v- abl , it is likely that this enzymatic activity of the BCR/ABL protein is involved in cellular transformation. Circumstantial evidence indicates that, at minimum, the production of an active P210 must confer some selective advantage on cells expressing it; the results presented in the chapter indicate no obvious reason for the t(9;22) to occur. Lacking contrary evidence, it can be assumed that many rearrangements may take place in cells that are genetically unstable.