Rhabdomyosarcomas comprise a biologically heterogeneous group of childhood malignancies that are histologically characterized by varying degrees of differentiation, ranging from uncommitted primitive mesenchymal cells to fetal myotubes. This differentiation pattern is reflected in the behavior of the tumor cells in vitro and can be manipulated by the addition of various biological and chemical agents to the intercellular milieu. Recent studies have documented some of the genetic and phenotypic events that occur under these conditions. In addition, the use of cell lines has facilitated the identification of characteristic karyotypic abnormalities and DNA transcriptional activators that are of potential diagnostic importance. Alterations of tumor-suppressor and multidrug-resistance genes have also been described, and they portend identification of susceptible families and potential therapeutic strategies to deal with this clinically aggressive family of childhood neoplasia. These developments herald an increasing utility of molecular biology in the diagnosis and treatment of pediatric sarcomas and necessitate pathologists' familiarity with this subject.