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Diagnosis of sarcoma increasingly relies on identifying genetic defects using modern molecular technologies. Each analytic method has unique advantages and specimen requirements that should be considered when allocating tissue for downstream testing. Karyotype on fresh tissue represents a genome-wide screen of gross chromosomal alterations, whereas fluorescence in situ hybridization and polymerase chain reaction detect specific defects that are characteristic of a given tumor type such as t(11;22) EWSR1-FLI1 in Ewing family tumors, t(X;18) SS18-SSX1 in synovial sarcoma, t(2;13) PAX3-FOXO1A in alveolar rhabdomyosarcoma, and MYCN gene amplification in neuroblastoma. Identifying a clonal genetic defect also provides a tumor marker that could help stage the extent of spread of the neoplasm or monitor the efficacy of therapy. In research laboratories, array-based methods identify genes and biochemical pathways contributing to tumor growth and maintenance, opening avenues for pharmacogenetic tests that predict which therapy is likely to overcome the biochemical defects with minimal toxicity. Array-based discoveries are also spurring validation of smaller test panels that rely on conventional technologies such as immunohistochemistry and reverse transcription polymerase chain reaction. The pathologist's expertize is critical in: (1) consulting with clinicians about specimen collection and handling; (2) preserving tissue for immediate testing and for any downstream testing that is indicated once morphology and immunophenotype are known; (3) performing tests that maximize outcome on the basis of the strengths and limitations of each assay in each available specimen type; and (4) conveying results to the rest of the healthcare team using proper gene nomenclature and interpreting the findings in a way that facilitates optimal clinical management.