Non-epithelial ovarian tumors are heterogeneous and account for approximately 10% of ovarian malignancies. The most common subtypes of non-epithelial ovarian tumors arise from germ cells or sex cord and stromal cells of the gonads. These tumors are usually detected at an early stage, and management includes surgical staging and debulking. When indicated for advanced disease, most respond to chemotherapy; however, options for patients with refractory disease are limited, and regimens can be associated with significant toxicities, including permanent organ dysfunction, secondary malignancies, and death. Targeted therapies that potentially decrease chemotherapy-related adverse effects and improve outcomes for patients with chemotherapy-refractory disease are needed. Here, we review the molecular landscape of non-epithelial ovarian tumors for the purpose of informing rational clinical trial design. Recent genomic discoveries have uncovered recurring somatic alterations and germline mutations in subtypes of non-epithelial ovarian tumors. Though there is a paucity of efficacy data on targeted therapies, such as kinase inhibitors, antibody–drug conjugates, immunotherapy, and hormonal therapy, exceptional responses to some compounds have been reported. The rarity and complexity of non-epithelial ovarian tumors warrant collaboration and efficient clinical trial design, including high-quality molecular characterization, to guide future efforts.