Increasing evidence supports the presence of a dynamic crosstalk between innate and adaptive immunity with a pivotal role played by pathways governing innate immune responses. TLRs (Toll-like receptors) and RLHs (retinoic acid-inducible gene I [RIG-I]-like helicases) are known to play a key role in these processes. A molecule of high significance in the protection against innate and adaptive immune aberrations is heme oxygenase 1 (HO-1). HO-1 is a microsomal enzyme that catalyses the degradation of heme to iron, carbon monoxide and bilirubin. These by-products appear to be the key mediators of its anti--inflammatory and cytoprotective action, mainly through the downregulation of pro-inflammatory and upregulation of anti-inflammatory molecules. Recent data from our lab support the presence of an additional direct effect of myeloid HO-1 on innate immune conditioning, and more specifically on the TLR3/TLR4/RIG-I pathway. In myeloid cells, HO-1 forms a complex with the transcription factor IRF3 (Interferon regulating factor 3) and is required for IRF3 phosphorylation and consequent type-I interferon and chemokine gene induction. Myeloid HO-1-deficient mice show reduced expression of IRF3 target genes and altered responses to infectious and organ-specific auto-immune diseases. This new frame of understanding HO-1 function should also be important for the future design of novel interventions differentially targeting the enzymatic versus the IRF3 modulating properties of HO-1.