Systemic fungal infections are an increasing problem in older adults. For several of the endemic mycoses, this increase is the result of increased travel and leisure activities in areas endemic for these fungi. Immunosuppressive agents, care in an intensive care unit, and invasive devices all contribute to infection with opportunistic fungi. Treatment of systemic fungal infections is usually with an azole or amphotericin B. The preferred regimen depends on the specific fungal infection, the site and the severity of the infection, the state of immunosuppression of the patient and the possible toxicities of each drug for a specific patient. In older adults, drug-drug interactions between the azoles and drugs commonly prescribed for older persons may lead to serious toxicity, and absorption of itraconazole can be problematic. Amphotericin B is associated with significant nephrotoxicity, especially in older adults with pre-existing renal disease, and infusion-related adverse effects. Newer lipid formulations of amphotericin B can obviate some of these toxicities, but their role in the treatment of systemic fungal infections in older adults has not yet been clarified.