Discoveries that SAMHD1 mutations cause Aicardi-Goutières syndrome (AGS) (Rice et al., 2009) and that SAMHD1 restricts HIV-1 replication in non-cycling immune cells (Baldauf et al., 2012; Berger et al., 2011; Descours et al., 2012; Hrecka et al., 2011; Laguette et al., 2011) established the role of SAMHD1 as an innate immunity factor involved in interferon signaling and retroviral restriction. Here, SAMHD1 is linked to Aicardi-Goutières syndrome.