Simple Summary: Rhabdomyosarcoma is a rare type of childhood cancer. Current treatment options include surgery, radiotherapy, and chemotherapy. Survival chances for RMS patients have increased over the last few decades as a result of improved risk-based patient allocation procedures in therapeutic protocols. However, RMS patients bearing an advanced disease at diagnosis still fare badly, and mortality rates remain very high. The novel chemotherapeutic combinations tested in clinical trials for RMS have failed to improve outcomes in this subset of patients. The impact of drug-metabolising enzymes (DMEs) on drug efficacy and their potential as targets for targeted therapy are sometimes overlooked. Here, we critically review the literature and what has been achieved in the treatment of RMS, with a focus on how DMEs modify patients' responses to therapy, and discuss new ideas towards the development of targeted therapies. Rhabdomyosarcoma (RMS) is a rare soft tissue sarcoma (STS) that predominantly affects children and teenagers. It is the most common STS in children (40%) and accounts for 5–8% of total childhood malignancies. Apart from surgery and radiotherapy in eligible patients, standard chemotherapy is the only therapeutic option clinically available for RMS patients. While survival rates for this childhood cancer have considerably improved over the last few decades for low-risk and intermediate-risk cases, the mortality rate remains exceptionally high in high-risk RMS patients with recurrent and/or metastatic disease. The intensification of chemotherapeutic protocols in advanced-stage RMS has historically induced aggravated toxicity with only very modest therapeutic gain. In this review, we critically analyse what has been achieved so far in RMS therapy and provide insight into how a diverse group of drug-metabolising enzymes (DMEs) possess the capacity to modify the clinical efficacy of chemotherapy. We provide suggestions for new therapeutic strategies that exploit the presence of DMEs for prodrug activation, targeted chemotherapy that does not rely on DMEs, and RMS-molecular-subtype-targeted therapies that have the potential to enter clinical evaluation. [ABSTRACT FROM AUTHOR]