The involvement of epigenetic aberrations in the development and progression of tumors is now well established. However, little is known of the epigenetic alterations in testicular cancer and particularly in platinum refractory germ cell tumors. Germ cell derived testicular cancers, as compared to somatic tumors, appear to have a unique epigenetic profile that features more extensive DNA hypomethylation. Emerging data from clinical specimens suggest that epigenetic aberrations, especially DNA hypermethylation, can contribute to chemotherapy resistance and poor clinical outcomes in testicular germ cell tumors. Recent data indicate that testicular cancer cells, even those resistant to platinum, are highly sensitive to low doses of demethylating agents. Based on these promising preclinical studies, we suggest that DNA methylation inhibitors in combination with chemotherapeutic agents may offer a path to overcome acquired drug resistance in testicular cancer, laying the foundation and rationale for testing this class of epigenetic drugs in the clinical setting. In this mini-review we provide a brief overview of the promise of DNA methylation therapy to treat patients with refractory cancer of the testes.