The incidence of HIV-related opportunistic infections (OIs) has declined in the United States with the increasing use of effective antiretroviral therapy for the treatment of HIV infection. However, the absolute number of patients with OIs remains high and there continues to be considerable associated mortality. OI guidelines from the National Institutes of Health, Centers for Disease Control and Prevention, and Infectious Diseases Society of America continue to be updated on a regular basis, several times per year, as optimal strategies for prevention and therapy evolve. Recommendations that have changed in these guidelines include: screening for cryptococcal antigen and treatment of asymptomatic antigenemia; empiric treatment of shigellosis infection in light of the recent spread of multidrug-resistant strains; the relative roles of vancomycin and metronidazole in diarrheal illness related to Clostridium difficile; and diagnosis of Pneumocystis jiroveci pneumonia (PCP; formerly Pneumocystis carinii pneumonia). This article summarizes a presentation by Henry Masur, MD, at the IAS-USA continuing education program held in Washington, DC, in May 2015.