The purpose of this exploratory study was to examine, from the perspectives of both HIV-infected children and such children's primary guardians, the barriers children face in adhering to combination antiretroviral therapies. Nine HIV-infected young children and 14 guardians of HIV-positive children were interviewed about what the children's lives were like, including the difficulties they faced in adhering to therapy, while taking antiretroviral medications. Results showed that children faced six main barriers to adherence related to (a) family daily routines; (b) medication side effects; (c) medication taste, size, and shape; (d) the stigma of HIV/AIDS; (e) medications as a reminder of HIV/AIDS; and (f) child deception. The findings underscore the difficult nature of the antiretroviral regimens and illuminate the daily obstacles children face in adhering to therapy. Interventions that target children's unique barriers are needed to improve adherence to antiretroviral medication regimens.