A myriad of changes are necessary to adapt to chronic hypoxemia. Key among these changes increases in arterial oxygen carrying capacity, ventilation and sympathetic activity. This requires the induction of several gene products many of which are regulated by the activity of HIF-1α, including HO-1. Induction of HO-1 during chronic hypoxia is necessary for the continued breakdown of heme for the enhanced production of hemoglobin and the increased respiratory and sympathetic responses. Several human HO-1 polymorphisms have been identified that can affect the expression or activity of HO-1. Associations between these polymorphisms and the prevalence of hypertension have recently been assessed in specific populations. There are major gaps in our understanding of the mechanisms of how HO-1 mediates changes in the activity of the hypoxia-sensitive chemosensors and whether HO-1 polymorphisms are an important factor in the integrated response to chronic hypoxia. Understanding how HO-1 mediates cardiorespiratory responses could provide important insights into clinical syndromes such as obstructive sleep apnea.