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Dendritic cells can be subdivided into three major subsets. The conventional (classical) dendritic cells (cDCs), also known as myeloid DCs, can be further split into the cDC1 and cDC2 subpopulations. The third subpopulation is the plasmacytoid DC (pDC). The pDCs are unique because they constitute the leukocyte, which secretes the largest amount of interferon (IFN). Since IFNs are crucial in the defence against viruses, it could be hypothesized that reduced IFN production by pDCs could cause susceptibility to viral infections in general. However, this does not seem to be the case, since it was not until the SARS-CoV-2 pandemic that the essential role of pDCs in viral immunity was revealed. In this review we discuss the role of pDCs in the protection against Covid-19 and the mechanisms underlying susceptibility when these cells are malfunctioning as seen in haematological malignancies. In contrast, overactive pDCs can lead to selected autoimmune diseases, where systemic lupus (SLE) is the premier example, demonstrating the yin and yang relationship.