Testicular germ cell tumors (TGCTs) are the most common cancer diagnosed in adolescent and young adult men in the US. TGCTs are considered to be a curable cancer, as patients are often cured of their disease with conventional chemotherapy regimens. The most common TGCTs often contain malignant pluripotent cells called embryonal carcinoma (EC) cells that self-renew and metastasize, as well as spontaneously differentiate into embryonic and extraembryonic tissues. Interestingly, despite TGCT incidence peaking in men 15-39 years old, TGCTs are believed to initiate from primordial germ cells (PGCs) during embryonic development. In a mouse model of malignant TGCTs, gPAK mice (germ-cell specific Pten and Kras mutant) develop malignant tumors containing EC and differentiated tissues representative of all three embryonic germ layers (teratoma). These tumors develop when Pten inactivating and Kras activating mutations are expressed in PGCs at embryonic day 12.5 (E12.5). Here, I report that germ cells are resistant to oncogenic transformation late in embryonic development, after E15, when their developmental potential is restricted. The unique genome maintenance mechanisms of pluripotent PGCs likely contribute to their susceptibility to oncogenic transformation and to the chemosensitivity of the tumors they develop into. Additionally, this gPAK mouse model was used to assess the efficacy of differentiation therapy in treating malignant TGCTs, as alternatives to the highly toxic cisplatin-based regimens are needed. Thioridazine, an FDA-approved anti-psychotic, was found to induce differentiation of EC cells in culture, which dramatically reduced their tumorigenic potential. Using multiple TGCT models, including the spontaneous gPAK model and a human xenograft model, it was shown that thioridazine treatment extends the survival of tumor-bearing mice, likely by eliminating the malignant EC component. It was also found that EC cells, both in vitro and in vivo, express and secrete miRNAs in the miR-290-295 cluster which can be used as biomarkers to detect malignant TGCTs. Together, these results demonstrate that pluripotency is an important feature in the etiology and clinical management of TGCTs. Pluripotency appears to determine germ cell susceptibility to oncogenic transformation and it is a feature of TGCTs that can be targeted for treatment and exploited for tumor detection.