Rhabdomyosarcoma (RMS) is a morphologically and clinically heterogeneous group of malignant tumors that resemble developing skeletal muscle and is the most common soft-tissue sarcoma in children and adolescents. The most prominent sites involve head and neck structures (~40%), genito-urinary track (~25%), and extremities (~20%). Embryonal (ERMS) and alveolar (ARMS) are the two major RMS subtypes that are distinct in their morphology and genetic make-up. The prognosis for this cancer depends strongly on tumor size, location, staging, and child's age. In general, ERMS has a more favorable outcome, whereas the mortality rate remains high in patients with ARMS, because of its aggressive and metastatic nature. Over the past two decades, researchers have made concerted efforts to delineate genetic and epigenetic changes associated with RMS pathogenesis. These molecular signatures have presented golden opportunities to design targeted therapies for treating this aggressive cancer. This article highlights recent advances in understanding the molecular pathogenesis of RMS, and addresses promising research areas for further exploration.