Toll-like receptors (TLRs) are phylogenetically well-conserved type I transmembrane proteins representing major pattern recognition receptors of the innate immune system for various pathogen-associated molecular patterns (PAMPs).1,2 Toll-like receptor signaling leads to activation of nuclear factor κB through the adaptor protein MyD88-dependent pathway and induces a battery of immune adjuvant effects, which are principally mediated by proinflammatory cytokines. Over the last 5 years, 11 TLR family members, along with their agonists, have been identified. Bacterial lipoproteins, lipoteichoic acid, and peptidoglycans have been shown to be agonists for TLR2/TLR1 and TLR2/TLR6. Toll-like receptor 3 binds double-stranded RNA synthesized by viruses, TLR4 recognizes bacterial lipopolysaccharide, TLR5 accepts bacterial flagellin, and TLR9 is activated by unmethylated cytosine guanine oligodeoxynucleotide motifs common to both bacterial and viral DNA (reviewed in Akira et al2). A recent addition to this list has been TLR11, which mediates the response to bacteria causing infections of the bladder and kidney.3 Toll-like receptor 7 and TLR8 are required for recognition of the viral single-stranded RNA.4,5 In addition, TLR7 and TLR8 are triggered by a family of low-molecular-weight synthetic compounds called imidazoquinolines.6 One of these is called imiquimod, a selective TLR7 agonist, which is currently licensed for the topical treatment of human anogenital warts in a 5% cream formulation (Aldara; 3M Pharmaceuticals, St Paul, Minn).7 Promising clinical results have also been obtained in open-label studies for the treatment of common warts, mollusca contagiosa,8 and skin tumors including bowenoid keratosis,9 actinic keratosis,10 lentigo maligna,11 and basal cell carcinoma.12 Although imiquimod can directly induce apoptosis of epithelial tumor cells in vitro13 and in vivo,14 the innate antiviral and antitumoral effects are the consequence of the induction of type I interferon (IFN)-α/β).15,16 Type I IFNs also shape the adaptive arm of the immune response by driving TH1 responses, either through direct action on T cells or through the promotion of dendritic cell maturation.17 In human peripheral blood, the principal producer of type I IFNs in response to imiquimod is represented by plasmacytoid dendritic cell precursors (PDCs),18,19 a novel subset of lymphoid-related cells selectively expressing high levels of TLR7 and TLR9.20,21 Plasmacytoid dendritic cell precursors are key players in innate antiviral immunity owing to their unique ability to produce large amounts of type I IFN.22,23 In addition, on viral stimulation, PDCs differentiate into dendritic cells with the ability to stimulate T-cell–mediated adaptive immunity.24,25 The unique link between innate and adaptive immunity has recently generated great interest in the use of imiquimod and other synthetic TLR agonists as adjuvants in cancer immunotherapy strategies.26 However, the observation that, in murine models, TLR activation may also trigger T-cell–mediated autoimmune disease recommends caution.27 We report herein a case of psoriasis exacerbated by topical imiquimod therapy, identify large numbers of PDCs in the dermal infiltrate of psoriasis, and suggest that, as IFN-producing targets of TLR-ligands such as imiquimod, PDCs may represent a crucial link between the innate and adaptive immune responses ultimately leading to psoriasis.