Before pDCs were discovered, IFN-I production during viral infections was believed to mainly occur in infected cells through the activation of intra-cytoplasmic sensors for viral RNA or DNA molecules such as the RNA-dependent protein kinase (PKR) or the more recently discovered RNA helicases RIG-I and MDA-5 [77] . However, pDCs are now known to be the major producers of IFN-I upon stimulation with herpesviruses as well as some other types of viruses in vitro, and also during in vivo infections with these same viruses [3, 12, 43, 46, 78] , while pDCs are most often not productively infected [4, 6, 13, 41, 79] . This apparent paradox was solved by the demonstration that pDCs express a unique set of endosomal receptors and associated signaling components allowing the detection of RNA or DNA sequences derived from engulfed viruses or infected cells. Indeed, pDCs express Toll-like receptors (TLR) 7 and 9 [80] which are localized in a specific endosomal compartment where they can respectively recognize single stranded RNA versus unmethylated CpG DNA sequences and consecutively initiate a signaling cascade ultimately resulting in high level IFN-I production. RNA or DNA molecules are not present in endosomes under steady state conditions in healthy individuals [81] . Thus, pDCs have the unique ability to detect viral infections without the requirement of endogenous viral replication, because they must be able to take up oligonucleotides from viruses or infected cells [82] into specialized endosomes for TLR7 or 9 triggering. The membrane receptors that must confer pDCs the ability to selectively recognize and engulf viral particles or apoptotic debris from infected cells remain to be identified.