Interferon Stimulated Genes (ISGs) play key roles in the control of viral life cycles. Understanding which ISGs have antiviral function and the molecular mechanisms responsible is critical to understanding viral host relationships and development of potential novel anti-viral strategies. Our research program has focused on the use of genome-wide and targeted CRISPR knockout (KO) and activator (CRISPRa) screens to identify host innate immune restriction factors with specific emphasis on Flaviviruses. CRISPR technology has revolutionised cell biology primarily through the KO of targeted alleles. However, CRISPRa has recently been developed to drive endogenous expression of the targeted gene of interest using a catalytically inactive Cas9 (dCas9) along with the recruitment of essential transcription helpers such as p65, HSF1 and HSV VP64. Using such CRISPRa screens we have identified known host innate immune restriction factors for Flavivirus infection such as IFI6 and IFNl2 and a novel protein ABCG8 that regulates intracellular cholesterol/sterol levels. Interestingly, CRISPRa activation of ABCG8 alone can activate ISG expression to control viral replication, suggesting that intracellular sensing of cholesterol can establish an antiviral state independent of IFN expression. We also used a CRISPRa specific ISG panel in several antiviral screen formats to test for the ability of ISGs to prevent viral induced CPE and genome replication (qRT-PCR) of a panel of Flaviviruses, hepatitis A virus and Human Coronavirus 229E. Our CRISPRa approach confirmed the anti-viral activity of ISGs like IFI6, IFNb and IFNl2 that prevented viral induced CPE, which was supported by high-content immunofluorescence imaging analysis. This work highlights CRISPRa as a rapid, agile, and powerful methodology to identify and characterise viral innate immune restriction factors that furthers our understanding of host control of viral infection.