Since the discovery of tumor necrosis factor (TNF)-alpha, researchers have pursued many approaches to harness the potency of TNF-alpha and TNF superfamily members to treat human cancers. Several ligands of the TNF superfamily, including TNF-alpha, lymphotoxin, FAS ligand (FasL), and APO2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) have been tested in various stages of clinical research for their anti-tumor efficacy. Moreover, several antibodies to TNF receptor (TNFR) superfamily members are now being explored as cancer therapeutics. Due to the toxicity associated with delivering TNF-alpha systemically at clinically relevant doses, more targeted methods are now seen as a likely alternative to provide a localized therapeutically effective dose of TNF-alpha. In this review we revisit historical attempts to use TNF-alpha to treat human cancer, and put this into the context of more recent targeted strategies to circumvent TNF-alphas systemic toxicity. We will attempt to integrate the results of pre-clinical and clinical trials with a concise synopsis of the TNF-alpha signaling network, with the goal of reconciling our understanding of how the cell biology and tumor biology mechanistically relate.