Rhabdomyosarcoma, the most common soft-tissue malignancy of childhood and adolescence, comprises a group of differing pathobiologic entities linked by their common propensity for formation of neoplastic skeletal muscle, a feature that results from biological forces related to aberrant transcription signals and the resultant production of myogenic proteins. At a molecular level, however, rhabdomyosarcomas form a heterogeneous group that can be subdivided into distinct clinicopathologic entities based on morphologic appearance and genetic makeup. These differing morphologic features were recognized in the mid-1900s by Horn and Enterline with their division of rhabdomyosarcomas into embryonal, alveolar, botryoid, and pleomorphic subtypes. More recent histologic and biologic studies have resulted in description of additional entities, such as spindle cell and anaplastic rhabdomyosarcoma, and refinements in recognition of the original entities, such as solid-alveolar rhabdomyosarcoma. Familiarity with newer classifications and their relationship to molecular aberrations is key to stratifying patients on current therapeutic protocols and proposed innovative genetic therapies.