Sarcomas include diverse mesenchymal neoplasms with widely varied prognosis, clinical behavior, and treatment. Owing to their rarity and histologic overlap, accurate diagnosis of sarcomas can be challenging. Our approach has evolved dramatically in the past few decades, where novel insights into the molecular pathogenetic basis for sarcomas has dramatically (re)shaped contemporary diagnosis, building on a largely morphology- and clinical presentation-based strategy. Examples include the introduction of novel immunohistochemical markers that serve as surrogates for molecular genetic alterations and identification of characteristic molecular alterations. Accordingly, cytogenetic and molecular genetic analyses, such as conventional karyotyping, fluorescence in situ hybridization, reverse transcription-polymerase chain reaction, and targeted sequencing, have increasingly been incorporated into the routine diagnostic work-up of these neoplasms. For those sarcomas with complex cytogenetic changes that lack specific alterations, additional testing is often directed toward identifying lines of differentiation and excluding pathognomonic (cyto-)genetic alterations. Although some gene rearrangements are diagnostic of particular sarcoma types, certain fusion partners, most notably EWSR1, are not tumor specific (and may, in fact, also be found in benign tumors). Correlation with clinical, radiologic, morphologic, and immunohistochemical findings is particularly important in tumors with such rearrangements to establish the correct diagnosis, acknowledging the inherent limitations of diagnostic tests. The recognition of sarcomas occurring in cancer predisposition syndromes is critical, with implications not only for the index patient but also potentially for family members, including the need for genetic counseling and sometimes particular types of surveillance. Together, contemporary sarcoma evaluation involves combining the initial morphologic evaluation with diagnostically relevant cytogenetic, molecular, and immunohistochemical testing methods.