Four years after the discovery of mouse plasmacytoid dendritic cells (pDC), pDC are still very much an 'enigmatic' cell type. It is clear that pDC are potent producers of type I IFN in response to viral, bacterial and even mammalian nucleotides. The role that they play in vivo before and after activation is still under scrutiny. This review concentrates on the pathways to activation of pDC, examining the activating ligands, receptors and signalling molecules that are known to be involved, and the relevance of these activation pathways to human disease.