Introduction: To evaluate systematically randomised clinical trials investigating non-opioid medications for the management and treatment of chronic breathlessness. Areas covered: The evidence for the role of benzodiazepines, anxiolytics, selective serotonin re-uptake inhibitors (SSRIs), tricyclic antidepressants, antihistamines, cannabinoids, nebulized furosemide and herbal-based treatments were critically reviewed. Search of the Clinical Trials Registry (Clinicaltrial.gov) identified ongoing studies expected to generate new data in the near future in several classes of non-opioid medications for their net effect on chronic breathlessness. Expert commentary: Morphine still has the best level of evidence for the symptomatic treatment of chronic breathlessness. Non-opioid treatments for chronic breathlessness are less studied than morphine and morphine-related medications although evidence is emerging in relation to some options. Currently, there is insufficient evidence to recommend non-opioids in the routine treatment of chronic breathlessness. There is a need to find agents, new as well as re-purposed, that can be used as alternative therapies to opioids for chronic breathlessness for people who are unable to tolerate morphine.