Tumor-specific chromosomal abnormalities are attracting a large interest owing to the diagnostic, prognostic, and therapeutic importance. The development of molecular techniques, e.g., fluorescence in situ hybridization (FISH), have improved the detection of specific chromosomal abnormalities in chronic lymphocytic leukemic (CLL). By using FISH, the problem with tumor cells with low mitotic rate is avoided since this method readily detects clonal aberrations also in nondividing, interphase cells. Three different types of probes are used: (1) centromeric probes for numerical chromosome abnormalities, (2) whole chromosome paints, and (3) locusspecific probes. The DNA probes are labeled with fluorochromes and the signals yielded are strong enough to enable analysis of interphase cells. These DNA probes may be directed towards any defined chromosomal region and this chapter will in detail describe the FISH method as a detector of trisomy 12 in CLL.