Tumour necrosis factor-alpha (TNF-alpha) is a potent immunomediator and proinflammatory cytokine that has been implicated in the pathogenesis of a large number of human diseases. The location of its gene with the major histocompatibility complex and biological activities have raised the possibility that polymorphism within this locus may contribute to the genetic association of this region of the genome with a wide range of autoimmune and infectious diseases. This review discusses the genetics of the TNF locus in several of the major autoimmune diseases and also in relation to infectious and neoplastic diseases. There is increasing evidence that genetic variation within the TNF locus is important in determining susceptibility to, or severity of, a significant number of these conditions.