Testicular Germ cell tumors (TGCT) represent the most common solid tumors affecting young men. They constitute a distinct entity because of their embryonic origin and their unique biological behavior. Recently, new preclinical data on genetic and epigenetic susceptibility profiles, biological signaling machinery as well as on molecular patterns of tumors and pathways of pathogenesis helped to elucidate the pathogenesis and the differentiation of TGCTs and to understand the mechanisms behind the development of resistance to treatment. In the present work, we have reviewed new clues to the development, differentiation and progression of TGCTs. We focus on the most important epigenetic and molecular biomarkers, and discussed their diagnostic and prognostic accuracy compared to the currently used biomarkers. The mechanisms underlying the development of resistance to cisplatin and commonly used chemotherapeutic agents are also discussed in detail. Finally, we summarize failed and ongoing clinical trials using targeted therapies in resistant TGCTs, and analyze the potential of new targeted therapies.