Plasmacytoid dendritic cells (PDC) are highly specialized immune cells capable of producing large amounts of type I and III IFN in response to viral infection. This response is mediated through TLR7 and TLR9 signalling pathways. In addition, PDC can differentiate into fully mature dendritic cells able to efficiently crosspresent viral antigens, thus playing an important role in adaptive immunity. This dual property of PDC is being used in clinical settings where synthetic TLR7 and TLR9 ligands are currently evaluated in clinical trials for the treatment of viral infections, allergies and cancers. Interestingly, there is evidence suggesting that chronic activation of PDC by endogenous RNA and DNA containing immune complexes maybe an important mechanism of driving autoimmunity and significant efforts to develop bi-functional antagonists of TLR7 and TLR9 are currently underway.