Dyspnea is one of the most common and distressing symptoms associated with cancer, occurring in nearly 70% of patients with advanced cancer and intrathoracic malignancies. Dyspnea is associated with impaired function, decreased quality of life, and shortened survival. Current therapies for dyspnea, such as supplemental oxygen and opioids, provide limited relief. Although dyspnea is more difficult to treat than pain is, few clinical trials of therapies for dyspnea have been conducted, and such trials are urgently needed to improve quality of life in cancer patients suffering from this condition. The long-term goal of our research is to develop evidence-based palliative therapies for dyspnea in patients with cancer. Corticosteroids may potentially improve the sensation of dyspnea by modulating the inflammatory response centrally and peripherally and decreasing swelling. On the basis of our preliminary data from a recent clinical trial, we hypothesize that high-dose dexamethasone is effective in treating cancer-related dyspnea. The overall objective of the proposed two-arm, double-blind, parallel (2:1), randomized, controlled trial is to compare the effect of dexamethasone with that of placebo on cancer-related dyspnea. The primary specific aim of this study is to compare the intensity of dyspnea in the dexamethasone arm with that in the placebo arm at week 1. In the second specific aim, we will compare the effects of dexamethasone with those of placebo in terms of personalized dyspnea response (based on a personalized dyspnea goal), unpleasantness of dyspnea, other symptoms, health-related quality of life, respiratory physiologic function, and adverse effects at week 1 and week 2, as well as the intensity of dyspnea at week 2. The third aim is to identify predictive markers of dyspnea response to dexamethasone. After obtaining surrogate consent, we will randomize patients to receive either dexamethasone or placebo twice daily for 2 weeks and monitor the patients closely. The proposed study is innovative in that it will cover a novel set of indications (i.e., both intensity and unpleasantness of dyspnea), patient population (i.e., patients with cancer), predictive makers (i.e., inflammatory biomarkers, respiratory physiologic function), and patient-reported outcome measures (i.e., personalized dyspnea response, Patient-Reported Outcomes version of the Common Terminology Criteria for Adverse Events instrument) for dexamethasone. The expected outcome of the proposed study is to establish dexamethasone as a treatment for dyspnea in patients with cancer. These results are expected to have an important positive clinical effect because the effective management of dyspnea will help improve patients' quality of life. This study will also increase our fundamental understanding of the pathophysiology of dyspnea, such as how dexamethasone improves inflammation and respiratory physiologic parameters, which may allow us to devise new and more effective, personalized treatments for this distressing symptom, ultimately moving the field of dyspnea research forward and shifting the treatment paradigm.