Context.—Small round cell tumors of soft tissue and bone constitute a divergent group of neoplasms. These lesions often demonstrate overlapping clinical and radiologic characteristics and share histomorphologic and sometimes immunophenotypic similarities, but they typically have diverse prognostic outcomes, thus warranting different clinical management. Recent advances in molecular and cytogenetic techniques have identified a number of novel molecular alterations contributing to the diversity of these lesions. This state-of-the-art knowledge has enhanced our understanding of these diseases. Objective.—To provide an overview of the current concepts in the classification and diagnosis of small round cell tumors of soft tissue and bone, focusing on salient histologic features, key immunophenotypic characteristics, and recent molecular genetic advancements. Data Sources.—Data were obtained from pertinent peer-reviewed English-language literature and firsthand experience from the authors as practicing bone and soft tissue pathologists. Conclusions.—Immunohistochemistry plays a vital role in rendering a specific diagnosis or narrowing the differential diagnosis in small round cell tumors of soft tissue and bone. Molecular genetic studies are often needed, especially for those lesions with unusual histologic features, an uncommon immunoprofile, and/or unusual clinical presentation. Accurate diagnosis of these tumors necessitates recognition of salient histologic features, judicious and astute use of ancillary studies, and correlation with the clinical and radiologic characteristics to guide clinical decision-making.