With increasing numbers of people traveling to high altitude for work or pleasure, there is a reasonable chance that many of these travelers have preexisting medical conditions or are receiving various medications at the time of their sojourn. As with all travelers to high altitude, they are at risk for altitude illnesses such as acute mountain sickness, high-altitude cerebral edema, and high-altitude pulmonary edema. While there are clear recommendations for pharmacologic measures to prevent or treat these illnesses, these recommendations are oriented toward healthy individuals and do not take into account the presence of preexisting medical conditions. In this review, we consider how the choice and dose of the medications used in the management of altitude illness-acetazolamide, dexamethasone, nifedipine, tadalafil, sildenafil, and salmeterol-are affected by a patient's underlying medical conditions. We discuss the indications and current dosing recommendations for individuals without underlying disease, and then consider how drug selection or dosing regimens will be affected by the presence of renal insufficiency, hepatic insufficiency, other important medical conditions, and the potential for serious drug interactions. We include comments about interactions with antimalarial medications and antibiotics used in the treatment of traveler's diarrhea, as well as the safety of use during pregnancy. By giving these issues adequate consideration, clinicians can increase the chances that properly evaluated patients with underlying medical conditions will enjoy a safe trip to high altitude.