The preponderance of mammalian resistance to infection is inher-ited rather than acquired. Even without lymphoid cells, mammals still protect themselves. They respond violently to bacteria, fungi, and viruses; or, more precisely, to specific molecular components of these organisms. Most of the molecular targets for recognition have been known for decades (1). However, only recently have the receptors and pathways for innate immune sensing been elucidated, and at that, only in part. The molecular basis of lipopolysaccharide recognition was established by positional cloning in 1998, with the identification of Toll-like receptor 4 (TLR4) as a highly specific, nonredundant receptor for lipopolysaccharide (2). This identification set the stage for the use of reverse genetic methods to establish the sensing functions of TLRs 1–3 and 5–9. Mouse TLR7 (3) and human TLRs 7 and 8 (4) sense imidazoquinolines, which are guanosine-based drugs that induce an antiviral response in vivo. TLRs 7 and 8 are close phylogenetic relatives that arose from a recent X-linked duplication event, and in the mouse, it is believed that TLR8 is biologically inactive, because animals lacking TLR7 are entirely unresponsive to imidazoquinolines. However, the natural (microbial) ligand (s) for TLRs 7 and 8 have remained a subject of considerable puzzlement. In what is surely a landmark piece of work, in a recent issue of PNAS Lund et al.(5) have provided the answer. Their data are concordant with those from two other laboratories, adduced independently (6, 7). We now have a more complete picture of what the TLRs do and are also left with several important questions, as discussed below.

TLRs 7, 8, and 9 form an evolutionary cluster (8), and TLR9 is a sensor for unmethylated DNA (9). TLR3, although evolutionarily distant from TLRs 7, 8, and 9, is a sensor for double-stranded (ds) RNA (10). TLRs 3, 7, 8, and 9 all seem to be located within the endosomes (11–13), and are targeted to the endosomes by structural features of the cytoplasmic domain (12). Stimulation of TLRs 7 or 9 causes a type I IFN response (Fig. 1). Both the TLR3 3 Trif pathway (14, 15) and the TLR9 3 MyD88 pathway are required for effective responses to mouse cytomegalovirus infection (16). Because TLRs 3 and 9 sense nucleoside-based ligands and are required for effective antiviral defense, because TLRs 3, 7, 8, and 9