Plasmacytoid monocytes (PM), originally described by pathologists as cells occurring in the interfollicular area of human lymph nodes, are emerging cells in the scenario of the immune system. PM normally circulate between peripheral blood, lymphoid organs and sites of inflammation using specific migratory pathways and signalling; PM are easily recognizable on the basis of their distinctive morphology and phenotype (CD3-, CD11c-, CD14-, CD20-, CD36+, CD56-, CD68+, CD123+, BD-CA2+). Recently it has been shown that PM produce high levels of type I interferon, thus corresponding to natural interferon-producing cells. Furthermore, PM or their precursors may differentiate in vitro towards a new subset of dendritic cells, supporting a function in antigen-dependent T cell priming. Taken together, these data suggest PM play a relevant role in the immune system, linking innate and acquired immunities. In fact, PM seem to be crucial in the pathogenesis of different immune-mediated human diseases including viral infections and autoimmune disorders, and to be involved in the immune control of some malignant neoplasms. The issue concerning the cell lineage of PM remains unresolved, but the frequent association between a tumoral expansion of PM and myelo-monocytic leukemia, together with cytogenetic identity between the two cell populations identified in rare cases, corroborates the myeloid origin of PM.