Despite increasing availability of anti-retroviral therapy, invasive cryptococcal disease continues to be a leading cause of death among HIV-infected individuals in resource-limited settings. Screening asymptomatic HIV-infected individuals with advanced immunosuppression for serum cryptococcal antigen clearly identifies a population at high risk of cryptococcal meningitis and death. However, screening with serum cryptococcal antigen alone identifies a heterogeneous clinical population, many of whom have mild clinical symptoms, sub-clinical meningeal infection, or fungemia. Currently, there is wide variation in practice and little evidence to guide the use of anti-fungal and anti-retroviral treatment for asymptomatic cryptococcal antigenemia (ACA). Furthermore, implementing a targeted screening and treatment intervention for ACA presents numerous operational challenges for already overburdened health care systems in resource-limited settings. While such an intervention shows promise, there are critical gaps in our understanding of ACA and its implications in the outpatient setting and an urgent need for additional research in this area.