The existence of sanctuary sites for human immunodeficiency virus type 1 (HIV-1) may potentially endanger the efficacy of antiretroviral therapy in the long term and may even make eradication of HIV-1 from the infected body impossible. Potential 'classic' sanctuary sites for HIV-1 are the central nervous system and the testes, but long-lived cell populations (such as macrophages) or latently infected (resting) CD4 cells may also be considered a sanctuary for HIV-1. These potential sanctuary sites, and putative underlying biochemical mechanisms such as the divergent phosphorylation properties of nucleoside reverse transcriptase inhibitors in different cell populations and the affinity of drugs for the multidrug transporter P-glycoprotein, are discussed.