Refractory dyspnea is breathing difficulty that persists at rest or with minimal activity despite optimal therapy of the underlying condition. Both endogenous (β-endorphin) and exogenous (morphine) opioids modulate the perception of dyspnea by binding to opioid receptors. Proposed mechanisms whereby opioids relieve refractory dyspnea include: decreasing respiratory drive with an associated decrease in corollary discharge; altering central perception; altering activity of peripheral opioid receptors located in the lung and decreasing anxiety. As patients respond variably to opioid therapy, a low dose of an opioid should be prescribed initially to manage refractory dyspnea. The dose should be titrated to achieve the lowest effective dose based on patient ratings of breathing difficulty. Research is needed to address clinical uncertainties and to identify genetic factors to improve the use of opioids to relieve refractory dyspnea.