The discovery that type I interferon (IFN)-inducible genes were strongly upregulated in peripheral blood in SLE over a decade ago sparked interest in understanding the relationship between type I IFN and SLE. Genome-wide association studies provide strong genetic evidence that type I IFNs are important for SLE risk. Of 47 genetic variants associated with SLE, over half (27/47, 57%) can be linked to type I IFN production or signaling. The recent identification of single gene mutations for disorders that share features with SLE – Aicardi–Goutières syndrome, chilblain lupus, and spondyloenchondrodysplasia – provide additional support for the hypothesis that type I IFNs are central drivers of SLE pathogenesis. These insights provide significant focus for efforts to tackle SLE therapeutically.