Tumor Necrosis Factor (TNF) is a pleiotropic cytokine with a central role in immune homeostasis, inflammation and host defence. Depending on the cellular context, TNF can induce diverse effects such as necrosis, apoptosis, differentiation, angiogenesis, cell migration and immune cell activation. Accordingly, TNF is believed to play a significant role in tumor development and progression; on the other side, this cytokine has potent antineoplastic activity both in experimental and clinical models. In the present chapter we provide a particular insight in the biology of TNF, emphasizing its tumor-related features, and discuss the experimental and clinical evidence available in the current literature supporting anticancer as well as cancer-promoting effects. Recent findings that may provide new alternatives to further exploit the anticancer power of TNF are also discussed.