Within the 'success story' of vertebrate evolution, the acquisition and refinement of the adaptive immune system is far from the least impressive example of co-evolution. Members of the tumour necrosis factor superfamily (TNFSF) and TNF receptor superfamily (TNFRSF) have crucial roles in both innate and adaptive immunity. Here, we propose a detailed description of the phylogenetic relations of the TNFSF and TNFRSF members and offer evidence that the divergence of the TNFSF and TNFRSF families paralleled the emergence of the adaptive immune system, at least partly through en bloc duplication. Unexpectedly, TNFSF subfamilies form monophyletic groups with shared functions, including TNFRSF usage. Finally, the mechanisms of (co-)evolution of TNFSF and TNFRSF are discussed.