Soft tissue sarcoma comprises 7.4% of childhood soft tissue malignancies with rhabdomyosarcoma (RMS) being the most common soft tissue sarcoma in children. RMS can arise in virtually any site in the body. Presenting symptoms depend on the site of origin of the tumor and can range from urinary obstruction or constipation in patients with pelvic or bladder/prostate tumors to proptosis in patients with orbital RMS, sinusitis symptoms in patients with parameningeal/sinus tumors, or a painless mass in extremity tumors. In North America there are about 350 new cases of RMS in children annually, with a similar number of new cases in Europe. The staging system for rhabdomyosarcoma has already been discussed in Chap. 5 and will not be repeated here. Risk stratification has evolved over the past several decades. Meza and colleagues analyzed patient and disease characteristics of patients with nonmetastatic RMS treated on the third and fourth Intergroup Rhabdomyosarcoma Studies and identified the prognostic significance of histology (alveolar (ARMS) and embryonal RMS (ERMS)), stage, group, and primary site (Meza et al. 2006) and resulted in stratification of patients into two low risk, one intermediate risk, and one high risk group for North American studies from 1997 to 2004. In Europe ongoing protocols use IRS Group, histology, patient age, primary tumor site, and size and nodal involvement to assign patients into four groups: low risk, standard risk, high risk, and very high risk. A multivariate analysis of risk factors in 788 patients with metastatic RMS treated in nine studies in Europe and North America from 1984 to 2000 identified age under 1 year or older than 10, unfavorable site of primary tumor, presence of three or more sites of metastatic disease, and presence of bone or bone marrow involvement as being correlated with inferior event-free survival (EFS) (Oberlin et al. 2008).Risk group assignment for therapy differs between European and North American trials, so comparison of outcomes for clinical trials needs to take this into consideration. For example, in the European trials, positive lymph nodes in patients with unfavorable histology and Group III tumors result in assignment of patients to very high-risk therapy, whereas they are treated as intermediate risk on Children’s Oncology Group (COG) trials. Many other COG “intermediate-risk” patients on the “D” series of studies were considered in European Pediatric Soft Tissue Sarcoma Group (EpSSG) or Cooperative Weichteilsarkom Studie (CWS) to be “high risk” (Sultan and Ferrari 2010).