Plasmacytoid dendritic cells (pDCs) are specialized APCs implicated in the pathogenesis of many human diseases. Compared with other peripheral blood mononuclear cells, pDCs express a high level of TLR9, which recognizes viral DNA at the initial phase of viral infection. Upon stimulation, these cells produce large amounts of type I interferon and other proinflammatory cytokines and are able to prime T lymphocytes. Thus, pDCs regulate innate and adaptive immune responses. This article reviews select aspects of pDC biology relevant to the disease pathogenesis and immunotherapy in multiple sclerosis. Many unresolved questions remain in this area, promising important future discoveries in pDC research.