Gastrointestinal opportunistic infections, primarily oral and esophageal candidiasis, are common in persons infected with the human immunodeficiency virus (HIV) and contribute significantly to morbidity and mortality. Research early in the AIDS epidemic established a strong association between the presence of oral and esophageal candidiasis in patients complaining of odynophagia, demonstrated the diagnostic efficacy of a therapeutic trial with anti-fungal medicines, and defined the indications for endoscopy in HIV-infected persons with upper gastrointestinal complaints. Resulting diagnostic and treatment strategies with anti-fungal agents were very effective in preventing and treating mycotic infections of the gastrointestinal tract. Now, robust data from the United States and Europe indicate that recent advances in the development and use of highly active anti-retroviral therapy (HAART) are associated with a striking decline in the prevalence of oro-esophageal candidiasis in HIV-infected persons. In addition to developing more effective, safer antiviral agents, an HIV vaccine, and other novel approaches to combating this illness, a major challenge is to provide HAART to those without access to these life-saving drugs.