Tumour necrosis factor (TNF) is a pro-inflammatory cytokine that signals through two distinct receptors, TNFR1 and TNFR2. TNF is essentially involved in the pathogenesis of various inflammatory and autoimmune diseases. Blocking TNF, in turn, has been proven to be highly effective in treating a variety of diseases. However, the role of its two receptors in these conditions is not very well understood. It is established that TNFR1 is mainly responsible for the detrimental effects of TNF. However, accumulating evidence suggests differential or even opposing effects of TNFR2 in the pathogenesis of a number of inflammatory and autoimmune conditions. In this review, we summarize the available data concerning biological and functional properties of the two TNF receptors and potential therapeutic consequences of these insights.