Management of soft tissue sarcoma is increasingly subtype-dependent. Surgery is recommended for uterine leiomyosarcoma, with trabectedin being the preferred option for advanced disease when the treatment goal is long-term tumor stabilization. Liposarcoma subgroups are characterized by distinctive morphologies and genetics, different patterns of disease progression and clinical behavior, and variable responses to treatment. Genetic analysis of sarcomas has provided insights into pathogenesis with potential for developing new molecular targets. At the cytogenetic level, soft tissue sarcomas are categorized into specific, balanced translocations and those due to massive chromosomal rearrangements. For subtypes such as undifferentiated sarcomas, angiosarcomas, alveolar soft part sarcomas and clear cell sarcomas, evidence is especially limited, although it is known that these tumors display markedly different sensitivities to chemotherapeutic and targeted agents.