The discovery of the Philadelphia chromosome in 1960, its subsequent characterization as a 9;22 translocation in 1973, and the cloning of the BCR and ABL1 genes that fuse as a result of the translocation opened the field of genomic medicine. The techniques of chromosomal analysis by G-banding and fluorescence in situ hybridization (FISH) that enabled researchers to make these discoveries are still commonly used today and remain invaluable means to diagnose and monitor many different constitutional and acquired diseases. Conventional cytogenetic analysis by G-banding permits the identification of numerical (gain or loss of a chromosome) and/or structural (translocation, deletion, inversion, etc.) abnormalities present in metaphase (dividing) cells. FISH can detect numerical abnormalities and characteristic gene fusions or rearrangements in interphase (nondividing) cells and additionally can detect abnormalities that may be cryptic (undetectable by G-banding). Whereas G-banding analysis provides a whole-genome view, FISH provides targeted analysis of only those genes or loci to which the probe is complementary. Each, however, has its place and can be used strategically to permit accurate diagnosis and therapeutic monitoring for minimal residual disease. In light of the rapid advances being made in genomic technologies such as array-based comparative genomic hybridization and next-generation sequencing, it is critical for clinicians and laboratorians to work together to determine the best testing algorithms for individual patients.