The lungs are a major target for various inflammatory, oxidative, carcinogenic or infectious stressors, which result in a range of lung diseases. Induction of heme oxygenase-1 (HO-1) during acute and chronic lung processes is a crucial defense mechanism. HO-1 catalyzes the degradation of free cellular heme to iron, carbon monoxide (CO) and biliverdin which is eventually converted to bilirubin by biliverdin reductase. In addition to the degradation of free heme, a pro-oxidant, HO-1 exerts anti-oxidant, anti-inflammatory and anti-apoptotic properties via its reaction products. This review summarizes the regulation and protective roles of HO-1 and its reaction products in several in vitro and in vivo lung disease models, including acute lung injury, ischemia-reperfusion (IR)-induced lung injury, cigarette smoke and chronic obstructive pulmonary disease (COPD), pulmonary arterial hypertension (PAH), lung cancer and asthma. The therapeutic applications of HO-1 in the lung as well as potential complications of excessive HO-1 induction are also covered. In summary, the HO-1 system is a powerful endogenous defense strategy with immense therapeutic potential against a range of lung diseases if optimal levels and tissue targeting can be achieved.