Progress in the systemic therapy of thymic malignancies has been hampered in the past by the rarity of this disease entity and the lack of a global collaborative effort in conducting phase II studies. Cisplatin-based therapy has been considered the standard of care, though data typically has been derived from a retrospective case-series approach. However, the arrival of novel cytotoxic agents and molecularly targeted agents into the clinic has helped provide the impetus for improved methodology in thymic malignancy research with an emphasis on more prospective phase II studies. This review discusses the results of traditional cytotoxic agents, novel cytotoxic agents, biologic therapy and the initial evaluation of molecularly targeted therapeutics, such as epidermal growth factor receptor inhibitors, for the treatment of thymic malignancies. In addition, potential novel targets such as VEGF, Bcl-2 and c-KIT are assessed.