Here, we will discuss: (1) how the shortcomings of CF lung immunity perpetuate inflammatory signaling and poor bacterial clearance; (2) the role of the HO-1/CO signaling pathway; and (3) the potential of CO-based therapy to reduce lung hyper-inflammation, counteract oxidative stress, and improve bacterial clearance, ultimately restoring lung homeostasis in CF lung disease. This evidence concerns the gene HMOX1 and cystic fibrosis.