Significant advances in our understanding of innate immunity have been made following the identification of three families of pathogen sensors: Toll-like receptors (TLRs), NOD-like receptors (NLRs) and RIG-I-like receptors (RLRs). Members of the TLR family recognize bacteria, viruses, fungi and protozoa; NLRs with known functions detect bacteria, and RLRs are anti-viral. It is likely that interplay between these families ensures the efficient co-ordination of innate immune responses, through either synergistic or co-operative signalling. Important interactions occur between TLRs and certain NLRs for inducing the pro-inflammatory cytokine interleukin (IL)-1β. TLRs induce pro-IL-1β production and prime NLR-containing multi-protein complexes, termed ‘inflammasomes', to respond to bacterial products and products of damaged cells. This results in caspase-1 activation and the subsequent processing of pro-IL-1β to its active form. In this article, we hypothesize that during the first phase of the host response to infection, an important interplay occurs between these families, providing a substantial combinatorial repertoire in innate immunity.