Sarcomas are infrequent malignant mesenchymal neoplasms characterized by notable morphological and molecular heterogeneity. At present, the diagnosis of sarcoma is based on morphology, immunohistochemistry, and clinicopathological correlation. Molecular studies in the clinical setting provide refinements to morphologic sarcoma classification, and contribute diagnostic information (frequently), prognostic stratification (rarely) and predictive information concerning specific therapies (occasionally). In this review, we summarize the major molecular mechanisms that underlie sarcoma pathogenesis, highlighting molecular alterations that provide diagnostic, prognostic or predictive information. The discussion focuses on representative mesenchymal tumor types, following a pathogenic classification combining cytogenetic / genomic information and molecular biologic features. We will address five major molecular alterations frequent in sarcoma, including 1) the presence of chimeric transcription factors, in vascular tumors; 2) abnormal kinase signaling, in gastrointestinal stromal tumor; 3) epigenetic deregulation, either by oncometabolites, as a result of metabolic enzyme mutations, or as primary events, in chondrosarcoma, chondroblastoma, and other tumor types; 4) deregulated cell survival and proliferation, due to extreme copy number alterations, in dedifferentiated liposarcoma; and 5) extreme genomic instability in conventional osteosarcoma, as a representative example of sarcomas with highly complex karyotype.