Heme oxygenase-1 (HO-1) is a critical stress-responsive enzyme that has antioxidant and anti-inflammatory functions. HO-1 catalyzes heme degradation, which gives rise to the formation of carbon monoxide (CO), biliverdin, and iron. The upregulation of HO-1 under pathological conditions associated with cellular stress represents an important cytoprotective defense mechanism by virtue of the anti-oxidant properties of the bilirubin and the anti-inflammatory effect of the CO produced. The same mechanism is hijacked by premalignant and cancerous cells. In recent years, however, there has been accumulating evidence supporting that the upregulation of HO-1 promotes cancer progression, independently of its catalytic activity. Such non-canonical functions of HO-1 are associated with its interaction with other proteins, particularly transcription factors. HO-1 also undergoes post-translational modifications that influence its stability, functional activity, cellular translocation, etc. HO-1 is normally present in the endoplasmic reticulum, but distinct subcellular localizations, especially in the nucleus, are observed in multiple cancers. The nuclear HO-1 modulates the activation of various transcription factors, which does not appear to be mediated by carbon monoxide and iron. This commentary summarizes the non-canonical functions of HO-1 in the context of cancer growth and progression and underlying regulatory mechanisms.