The advent of HAART has had a profound effect on HIV/AIDS and its associated complications such as HAD, HIVE and MND. However, to further improve the morbidity associated with this destructive pandemic, methods to circumvent the brain barriers must be accomplished so that sufficient concentrations of anti-HIV drugs can enter the brain. As several studies have acknowledged, this is not an easy task and its difficulty, at least in part, is attributed to the powerful transporters present at both the blood–brain and blood–CSF barriers. Members of the ABC and SLC transporter superfamilies act in concert to protect the brain and consequently restrict the entry of anti-HIV drugs into the brain (Table 3). Several factors add to the complexity of the problem, such as the multi-specificity of the transporters, the diverse expression profiles of transporters in different tissues (e.g. the BBB compared with the choroid plexus), the changing expression of transporters as a consequence of HIV infection and differences between the viral populations in the CNS and the plasma, making treatment immensely difficult. A thorough understanding of each transporter, its location, level of expression and transport potency is needed to help improve the treatment of HIV infection and AIDS.