Drug delivery to solid tumors is one of the most challenging aspects in cancer therapy. Whereas agents seem promising in the test tube, clinical trials often fail due to unfavorable pharmacokinetics, poor delivery, low local concentrations, and limited accumulation in the target cell. A major step forwards in the treatment of solid tumors is the recognition of the tumor-associated vasculature as an important target for therapy. Inhibition of tumor vascular development has a direct effect on the growth and progression of the tumor. Destruction of an existing vasculature also directly inflicts serious damage to the tumor cell. Moreover, the tumor vascular bed can be manipulated facilitating enhanced permissiveness of the tumor for administered chemotherapeutics. In this review, we focus on the use of tumor necrosis factor alpha (TNF) in local and systemic therapy in conjunction with chemotherapy. In these settings TNF demonstrates potent and selective activity on the tumor vascular bed, which strongly improves tumor response.