Multimodality treatment including chemotherapy, surgery, and radiation therapy dramatically improved the survival of children with sarcomas. Unfortunately, approximately 20–30% of children with localized disease at diagnosis experience a recurrence. The prognosis for both children with recurrent disease and children with metastatic disease at the time of initial diagnosis remains quite poor. Furthermore, the most effective therapies are complicated by a host of acute and long-term toxicities. Given this, the development of novel agents remains a top priority for researchers in the field of pediatric oncology. The focus of anticancer drug discovery and development has shifted away from chemotherapy to newer classes of drugs that are more targeted to the tumor or tumor microenvironment. The development of these treatments and selection for their use in pediatric sarcomas are based on the oncogenic role of the therapeutic target, which varies by tumor type. These novel therapies either selectively target proteins and/or signal transduction pathways that are directly involved in the development and maintenance of the malignant phenotype or exploit the immune system to eradicate malignant cells. In this review, we focus on the current evidence that supports the use of small-molecule inhibitors, immunotherapy, and novel targeted chemotherapeutic approaches for the treatment of pediatric sarcomas.