Resting CD4+ T-cells are critical for establishing HIV-1 reservoirs. It has been known for over two decades that resting CD4+ T-cells are refractory to HIV-1 infection, but the underlying mechanisms are not fully understood. Compared with activated CD4+ T-cells that support HIV-1 infection, resting CD4+ T-cells have lower levels of dNTPs, which limit HIV-1 reverse transcription. The dNTPase SAMHD1 has been identified as an HIV-1 restriction factor in non-cycling myeloid cells. Two recent studies revealed that SAMHD1 restricts HIV-1 infection in resting CD4+ T-cells, suggesting a common mechanism of HIV-1 restriction in non-cycling cells that may contribute to viral immunopathogenesis.