Human plasmacytoid dendritic cells (pDC) are crucial for the modulation of adaptive immune responses in the course of neoplastic, viral and autoimmune diseases. In several of these disorders deregulated pDC-derived interferon-α (IFN-α), a key cytokine produced by pDC, plays a central role. Apart from IFN-α, pDC can produce a variety of other mediators, which are involved in immunological cross-talk. The most recently discovered are the cytotoxic serine protease granzyme B (GrB) and indoleamine 2,3-dioxygenase, which have been described to be involved in the suppression of effector T cell responses. Here we review the regulation of pDC function by a variety of immunomodulatory agents, which may be developed as future candidates for the therapy of a variety of diseases. Moreover, we introduce the novel concept of enhancing immune responses after vaccination in poor responders by increasing pDC-derived IFN-α and simultaneously inhibiting pDC-derived GrB secretion. Finally we discuss potential approaches to abrogate pDC-mediated tolerance induction against tumors and viral infections.