To study tumor therapeutic treatment modalities, whether from a clinical, preclinical, or fundamental point of view, the use of clinically relevant animal models is indispensable. Particularly when the treatment comprises a multitargeted approach, (e.g., both tumor cells and endothelial cells are targeted), the in vitro data will be of very limited value. Well-chosen animal models will provide conclusive data on the activity of the drug in the complex in vivo setting. Moreover, when the treatment targets the stromal compartment of the tumor rather than the tumor cells directly, insight into the mechanism of action is only possible when studied in vivo. This approach is of great importance for studies on the use of tumor necrosis factor-α (TNFα) in solid tumor therapy. Although TNFα has shown activity toward tumor cells in vitro directly, we and others have demonstrated that an important activity of this cytokine is directed toward the tumor vasculature. To elucidate the working mechanism of TNFα and to test possible treatment modalities, the animal models described here are crucial. In this chapter we will describe the use of specific animal models for efficacy studies, such as isolated limb perfusion and isolated liver perfusion in the rat.