Small cell carcinoma of the ovary, hypercalcemic type (SCCOHT), is a rare yet highly aggressive malignancy with a poor prognosis. Currently, there are no SCCOHT treatment guidelines. After surgery, many patients with SCCOHT receive adjuvant cisplatin and etoposide (CE), based on its efficacy in small cell lung cancer (SCLC). Nonetheless, CE-refractory SCCOHT is still common. Novel therapies (ie, histone deacetylase [HDAC] inhibitors) are being studied as they may target abnormal chromatin remodeling known to be associated with SCCOHT. We present the case of a 21-year-old female with Stage IC SCCOHT status after unilateral oophorectomy. Despite adjuvant CE, the patient developed disease progression. This is the first case report of a patient with CE-refractory SCCOHT treated with second-line topotecan (a topoisomerase-1 inhibitor) and romidepsin (an HDAC inhibitor). Although our patient's SCCOHT further progressed and lead to her death, her story highlights the importance of discovering better therapeutic targets for the treatment of SCCOHT.