When the tumour necrosis factor-alpha (TNF-alpha) gene was cloned the protein became available for use in clinical trials as an antineoplastic agent. However, side effects have severely limited its application in cancer treatment. Studies on the species specificity of TNF have indicated that the p75 TNF receptor (TNFR75) may play an important role in the generation of these side effects in humans. Using human TNF mutants with selective receptor-binding properties it has been demonstrated in neutrophils and endothelium that TNFR75 is involved in the mediation of the proinflammatory activity of TNF by facilitating the p55 TNF receptor (TNFR55). However, only TNFR55 appears to be involved in mediating TNF cytotoxicity. Therefore the potential exists for the successful reintroduction of TNF-alpha, in the form of TNFR55-selective mutants, into the clinical arena with the promise of reduced side effects.