Toll-like receptors (TLRs) are key components of the innate immune system, functioning as pattern recognition receptors that recognise a wide range of microbial pathogens. TLRs represent a primary line of defence against invading pathogens in mammals, plants and insects. Recognition of microbial components by TLRs triggers a cascade of cellular signals that culminates in the activation of NFkappaB which leads to inflammatory gene expression and clearance of the infectious agent. The history of NFkappaB began with the TLR4 ligand lipopolysaccharide (LPS), a component of the cell wall of Gram-negative bacteria, since this was the stimulus first used to activate NFkappaB in pre-B-cells. However, since those early days it has been a circuitous route, made possible by drawing on information provided by many different fields, that has led us not only to the discovery of TLRs but also to an understanding of the complex pathways that lead from TLR ligation to NFkappaB activation. In this review we will summarize the current knowledge of TLR-mediated NFkappaB activation, and also the recent discoveries that subtle differences in kappaB binding sequences and NFkappaB dimer formation result in specific gene expression profiles.