SAMHD1 is the latest in the ever-growing list of HIV restriction factors. A new study by Lahouassa et al. shows that this host factor prevents HIV from infecting dendritic and other myeloid cells by reducing levels of intracellular dNTPs. When SAMHD1 was first identified as an HIV restriction factor in 2011, its mechanism of action was unclear. Subsequently, it was identified as a deoxynucleoside triphosphate triphosphohydrolase, which converts dNTPs into deoxynucleosides and inorganic triphosphates. Lahouassa et al. now link this enzymatic activity to suppression of HIV. Knocking down SAMHD1 in myeloid cells increased free dNTP levels, rendering the cells permissive for HIV infection. Conversely, increased expression of SAMHD1 decreased both dNTP levels and permissiveness to HIV infection. This work reveals a new facet of innate immunity: viruses that replicate through a DNA intermediate can be inhibited by limiting levels of free dNTPs. Thus, drugs that decrease available dNTP pools may be therapeutically useful not only for retroviruses but also for adenoviruses, papillomaviruses and herpesviruses. (Nat. Immunol. 13, 223–228, 2012)