The interferon regulatory factor (IRF) family of transcription factors play a vital role in the human innate antiviral immune responses with production of interferons (IFNs) as a hallmark outcome of activation. In recent years, IRF3 has been considered a principal early regulator of type I IFNs (TI-IFNs) directly downstream of intracellular virus sensing. Despite decades of research on IRF-activating pathways, many questions remain on the regulation of IRF3 activation. The kinases IκB kinase epsilon (IKKε) and TANK-binding kinase-1 (TBK1) and the scaffold proteins TRAF family member-associated NF-kappa-B activator (TANK), NF-kappa-B-activating kinase-associated protein 1 (NAP1) and TANK-binding kinase 1-binding protein 1 (TBKBP1)/similar to NAP1 TBK1 adaptor (SINTBAD) are believed to be core components of an IRF3-activation complex yet their contextual involvement and complex composition are still unclear. This review will give an overview of antiviral signaling pathways leading to the activation of IRF3 and discuss recent developments in our understanding of its proximal regulation.