Cytogenetic analysis plays a direct, potentially decisive role in the examination of benign and malignant bond and soft tissue tumors. Translocations, or the exchange of chromosomal material between two or more nonhomologous chromosomes, are frequently encountered as tumor-specific anomalies in mesenchymal neoplasms. The consequences of many of these translocations has been the formation of chimeric proteins with features characteristic of altered transcription factors. Recent studies have revealed new tumor-specific translocations (eg, cemento-ossifying fibroma and myxoid chondrosarcoma) and the association of established translocations, eg, t(11;22) and t(12;16), in rare histologic subtypes such as biphenotypic sarcomas with myogenic and with neural differentiation and round cell liposarcoma, respectively. In contrast to a single translocation, many mesenchymal neoplasms such as malignant fibrous histiocytoma and osteosarcoma are characterized by multiple, often complex, chromosomal abnormalities. Recent advances in molecular cytogenetics, eg, in situ hybridization and comparative genomic hybridization, have made the identification of many of these abnormalities possible and in some instances, have revealed chromosomal imbalances not detectable with traditional cytogenetic analysis.