The immunoregulatory transcriptional modulators – IFN‐regulatory factor (IRF)‐3 and IRF‐7 – possess similar structural features but distinct gene‐regulatory potentials. For example, adenovirus‐mediated transduction of the constitutively active form of IRF‐3 triggered cell death in primary human MΦ, whereas expression of active IRF‐7 induced a strong anti‐tumoral activity in vitro. To further characterize target genes involved in these distinct cellular responses, transcriptional profiles of active IRF‐3‐ or IRF‐7‐transduced primary human MΦ were compared and used to direct further mechanistic studies. The pro‐apoptotic BH3‐only protein Noxa was identified as a primary IRF‐3 target gene and an essential regulator of IRF‐3, dsRNA and vesicular stomatitis virus‐induced cell death. The critical role of IRF‐7 and type I IFN production in increasing the immunostimulatory capacity of MΦ was also evaluated; IRF‐7 increased the expression of a broad range of IFN‐stimulated genes including immunomodulatory cytokines and genes involved in antigen processing and presentation. Furthermore, active IRF‐7 augmented the cross‐presentation capacity and tumoricidal activity of MΦ and led to an anti‐tumor response against the B16 melanoma model in vivo. Altogether, these data further highlight the respective functions of IRF‐3 and IRF‐7 to program apoptotic, immune and anti‐tumor responses.