Inflammation importantly contributes to the pathophysiology of Cardiovascular Disease (CVD). Signal Transducer and Activator of Transcription (STAT)1 operates at the frontier of innate and adaptive immunity and its involvement in CVD has been widely appreciated. A unique role of STAT1 in cross-talk between the pro-inflammatory cytokine IFNγ and TLR4 activators (TLR4-A) has been uncovered in immune as well as vascular cells increasing inflammation. Interferon Regulatory Factor (IRF)8 whose expression was initially identified in immune cells, controls development and differentiation in close connection with PU.1. In addition, as a STAT1-target, IRF8 accounts for “immune cell-specific” STAT1-dependent functions of IFNγ and LPS. Novel studies prove that also in endothelial cells (ECs) and vascular smooth muscle cells (VSMCs), STAT1 and IRF8 orchestrate a transcriptional platform for cross-talk between IFNγ and TLR4-A, which leads to amplified pro-atherogenic responses in the vasculature. In addition to its known immune cell functions, this points to a novel “inflammation-dependent” role of IRF8 in vascular cells. In this review we present a summary of these findings and postulate STAT1- and IRF8-target genes as promising markers of vascular inflammation, and STAT1 and IRF8 as potential targets for the development of new immunosuppressive and anti-inflammatory agents for the treatment of CVD.