The activation of Toll-Like receptors (TLRs) and Nod-like receptors (NLRs) triggers intracellular signalling pathways that lead to effector mechanisms in innate immunity and inflammation. The negative regulation of TLR signalling has been extensively studied. Current areas of research include post-transcriptional regulation by miRNA, post-translational regulation by ubiquitination and regulation by splice variants such as MyD88s, TRAM adaptor with GOLD domain and IRAK2 isoforms. The negative regulation of NLR signalling is a relatively new area of research. Examples include a splice variant of NOD2, the ubiquitin editing enzyme A20, pyrin domain-only proteins and caspase recruitment domain-only proteins which all have a negative effect on NOD2 or NLRP3 signalling. A greater understanding of the mechanisms underlying the negative control of TLR and NLR signalling may provide new targets for therapeutic intervention.