A long-standing question in the HIV field is why HIV-1 fails to replicate in resting CD4(+) T cells. A new study shows that host deoxynucleoside triphosphate triphosphohydrolase (dNTPase) sterile α motif and histidine/aspartic domain-containing protein 1 (SAMHD1), previously shown to block HIV infection in myeloid cells, also restricts HIV replication in resting CD4(+) T cells by hydrolyzing dNTPs, which are needed for reverse transcription of the virus (pages 1682-1687).