Classical cytotoxic treatment of rhabdomyosarcoma (RMS) is often accompanied by significant morbidity and poor response. This cytotoxic therapy may induce a multidrug resistance (MDR) phenotype in RMS which is associated with decreased effectiveness of chemotherapy. The majority of MDR molecules belong to a family of ABC (ATP binding cassette) transporters. Studies of drug resistance in RMS suggest that there are various mechanisms acting simultaneously, which might explain the low percentage of long-term survival in this malignancy. Moreover, although cells exposed to cytotoxic agents increase expression of muscle differentiation markers indicating myogenic differentiation, multidrug resistance may be a major obstacle in differentiation therapy for RMS. This review briefly discusses the current knowledge of resistance in RMS and emphasizes the importance of understanding the different aspects of MDR status in these patients.