Oxygen is a powerful substrate and signal. The ability to understand and control this vital substance will open new avenues of therapy for multiple diseases. New insights into cutaneous oxygenation suggest that there may be a sound basis for topical oxygen therapy. The indications for systemic oxygen therapy are expanding as well, as research delves into the role of oxygen in pathophysiologic conditions. Previous therapeutic approaches simply relied on providing oxygen as a critical substrate for fundamental metabolic processes. New therapies that also utilize oxygen as a needed signal will further expand the indications for oxygen therapy.