While attention has been mainly drawn on the goods of pDC responses to herpesviruses, one should not ignore the possibility that pDCs may also contribute to disease for given herpesviruses in specific physiopathological contexts. From this point of view, it is revealing that for infections with HIV-1 or SIV, a paradigm shift recently occurred regarding the role of pDCs in the disease. In contrast to the initial hypothesis that pDC responses should be protective, the current idea is that pDCs play an important deleterious role in the development of the disease. In the mouse model of MCMV infection, pDC hyperactivation can contribute to induce a transient suppression of antiviral adaptive immunity likely due in part to deleterious effects of high systemic levels of IFN-I on cDCs or CD8 T cells. pDCs have also been shown to be involved in a variety of autoimmune diseases for which infections with certain herpesviruses may constitute possible triggering agents. Under these physiopathological settings, therapeutic strategies aimed at dampening pDC activation may yield a clinical benefit.