Rhabdomyosarcoma (RMS) is the most common soft-tissue sarcoma of childhood, with an annual incidence of 4 to 7 cases per million children. RMS comprises a heterogeneous family of tumors related to the skeletal muscle lineage. The tumors are conventionally divided into two major histologic subtypes, embryonal (ERMS) and alveolar (ARMS). ERMS typically occurs in children less than 10 years of age, most frequently in the head and neck, genitourinary tract, and the retroperitoneum. Chromosomal analyses of RMS cases demonstrated nonrandom translocations associated with the ARMS subtype. The genetic syndromes with isolated reports of RMS include Klinefelter syndrome, Duchenne muscular dystrophy (DMD) cardio-facio-cutaneous syndrome (CFCS) and Noonan syndrome. Both Noonan syndrome and CFCS share some features of Costello syndrome. While Noonan syndrome has been linked to an increased risk of other malignancies, Klinefelter, CFCS, and DMD are not thought to be cancer predisposition syndromes.