Toll-like receptors (TLRs) are sensors of foreign microbial products, which initiate host defense responses in all multicellular organisms examined to date. They are the target for most adjuvants, are essential for the establishment of memory in T and B cells and provoke inflammation. They program dendritic cells in their interaction with Th1 cells and their signalling pathways enable a tailoring of host defense responses to the provoking microbe previously unsuspected in the innate arm of immunity. Their discovery and characterisation fills a void in immunology and is the culmination of an effort that began with one of immunology's founding fathers, Elie Mechnikov. Targeting TLRs therapeutically now has the potential to impact on how we treat infectious and inflammatory diseases.