Tumour Necrosis Factor (TNF) is a cytokine initially discovered for its capacity to induce haemorrhagic necrosis of experimental tumours and later found to be endowed with potent proinflammatory activities. It was soon realised that these latter properties were at the origin of unacceptable systemic toxicity in all trials aimed at exploiting the anti-tumour activities of TNF. The present review intends to reconsider the efforts that have been devoted over the past ten years to increase the therapeutic index of TNF so to make it a useful drug for the treatment of malignancies. Overall, attempts to achieve this goal with systemically administered TNF have met little success so far. On the other hand, impressive results have been obtained with locoregional administration of TNF. Although of relatively limited clinical utility, these observations have indicated a realistic possibility for a therapeutic exploitation of TNF in tumour therapy: the delivery of systemically administered TNF to the site of tumour growth. On this basis, different targeting and pre-targeting strategies have been developed to achieve this goal. While still in their infancy, these approaches have yielded encouraging results in experimental tumour models. In the forthcoming years it will be possible to evaluate if they represent a practicable means of delivering high doses of TNF to the tumour while sparing the organism from systemic, toxic effects.