Refractory breathlessness is one of the most common and devastating symptoms of advanced cardiorespiratory disease, both malignant and nonmalignant. In spite of increased interest in research in the last 20 years, there have been few significant advances in the palliation of this distressing condition. The most successful palliative regimens for breathlessness always include pharmacological and nonpharmacological interventions used concurrently. When patients are active, nonpharmacological treatments (e.g., exercise) are the most effective. As the patient becomes more breathless, eventually becoming breathless at rest, pharmacological treatments become more important. Opioids have the most extensive evidence base to guide their use. Other pharmacological interventions may act partly by helping breathlessness (by mechanisms still uncertain) or by treating concomitant precipitating and exacerbating conditions, such as depression and anxiety. A specific treatment to palliate breathlessness remains elusive. The neurophysiological substrate of breathlessness perception is still relatively poorly understood and not well reproduced in animal models. Research using functional MRI and other imaging, with more precise clinical trial methods, may help to bring significant advances. In the next 5 years, novel approaches to delivering opioids may be developed, the effective use of inhaled furosemide may be elucidated and the place of antidepressants and anxiolytics will become clearer. A role for cannabinoids may emerge. New drugs may be developed as our understanding of neurophysiology grows.