Over the past several years, the application of a spectrum of cytogenetic and molecular diagnostic techniques has dramatically improved our understanding of the pathophysiology of leukemia. These techniques include chromosomal translocations visualized by G-banding techniques, fluorescence in-situ hybridization, spectral karyotyping, comparative genomic hybridization, loss of heterozygosity analysis, and characterization of point mutations by DNA sequence analysis. We will review the application of these techniques, update novel findings utilizing these techniques over the past year as they apply to specific leukemias, and review the clinical and therapeutic implications of these findings.