Zygomycosis, an uncommon but frequently fatal mycosis caused by fungi of the class Zygomycetes, develops most commonly as an opportunistic disease. Successful therapy involves a combined approach based on early diagnosis, prompt institution of medical therapy, and extensive surgical debridement of all devitalized tissue. Given the rarity of this condition, novel therapeutic strategies have been limited and only tested on an individual basis. The use of high-dose lipid formulations of amphotericin B, prompt reversal of the underlying predisposing condition, and hyperbaric oxygen are the most common strategies that have shown potential value in the treatment of zygomycosis.