Members of the Toll-like receptor 9 (TLR9) subfamily are evolutionarily related and sense viral and bacterial infections at the endosomal subcellular compartment. Whereas TLR9 directly recognizes as ligands viral and bacterial CpG-DNA motifs, murine TLR7 and human TLR8 sense viral single stranded RNA motifs. Upon ligand-driven activation, members of the TLR9 subfamily bridge innate and adaptive immunity by activating immature antigen-presenting dendritic cells into professional antigen-presenting cells in a T helper cell-independent fashion. Cellular activation is strictly dependent on the adaptor molecule MyD88, as opposed to activation mediated by the TLR2-4 subfamilies, in which the adaptor molecules TIRAP, TRIF and TRAM come into play.