Lymphoma is a neoplasm of the immune system cells and their precursors. Despite their common origin from bone marrow, these tumors exhibit a wide range of immunological and genetic characteristics, which reflect the diversity of their normal counterpart cells. Lymphoid malignancies arise from both B and T cell compartments of the immune system. The cytogenetic analysis of lymphomas is hampered by the low yield and poor quality of metaphase spreads. More recently however, the application of techniques such as FISH and PCR, for which culturing of tumor cells is not a pre-requisite, has improved the characterization of lymphomas at the genetic level. Chromosomal translocations have an established role in diagnosis, prognosis, and prediction of response to treatment in haematologic and lymphoid malignancies. FISH, the assay of choice for localization of specific nucleic acids sequences in native context, is a 20-year-old technology that has developed continuously. Over its maturation, various methodologies and modifications have been introduced to optimize the detection of DNA and RNA.