This chapter discusses the molecular and genetic characterization of human tissue tumors. Tumor development is a multistep process requiring the mutation of several genes for the expression of the fully malignant phenotype. Soft-tissue is a nonepithelial extraskeletal tissue of the body exclusive of the reticuloendothelial system, glia, and supporting tissue of various parenchymal organs. Soft-tissue tumors are a heterogeneous group of tumors that arise as soft-tissue masses and usually exhibit the differentiated features of adult soft tissue. The major histogenic categories of malignant soft-tissue tumor include leiomyosarcoma, rhabdomyosarcoma, liposarcomas, and malignant peripheral nerve sheath tumors. The development of the human soft-tissue tumors are unknown but a variety of causes have been suggested, including exposure to chemical carcinogens and radiation, physical trauma, immunological factors, and constitutional genetic abnormalities. Major changes in the classification of soft-tissue sarcomas and improvements in diagnosis through the use of new immunohistochemical reagents and refinements in ultrastructural analysis have been made. Some common occurring tumors are fibromatosis, Li–Fraumeni syndrome, Von Recklinghausen's Neurofibromatosis, sarcoma in retinoblastoma families, Beckwith–Wiedemann syndrome, and benign tumors. The tumor etiology, genetic susceptibility to soft-tissue tumors, gene amplification, and chromosomal abnormalities are also discussed in the chapter.