Summary: The interleukin-1 receptor (IL-1R)/Toll-like receptor (TLR) superfamily was first defined in 1998 as a family of proteins that contain the Toll-IL-1 receptor domain. At that time, there were a number of orphan receptors in the IL-1R branch, and the TLRs had yet to be shown to be key innate immune receptors that sense microbial products. We now know a great deal more about this superfamily, with the description of novel IL-1 family members such as IL-1F6 signaling via IL-1Rrp2 and IL33 signaling via ST2. Remarkable progress has been made in our understanding of the functions of the TLRs, leading to a renaissance of interest in innate immunity. The importance of IL-1 is also being rediscovered, with the observation that Nalp3 is a key regulator of caspase-1, the enzyme that processes pro-IL-1β into the mature cytokine. This area has therefore proved very fruitful in terms of improving our knowledge of the molecular basis for innate immunity and inflammation, and we can anticipate further discoveries in the coming years.