HIV-1 infection can now be treated effectively in many patients in the developed world, using combination antiretroviral therapeutics, called highly active antiretroviral therapy (HAART). Nevertheless, these regimens do not cure HIV-1 infection. Residual disease is maintained via proviral latency in resting CD4+ T-lymphocytes and possibly monocytes/macrophages. In addition, low-level viral replication continues in a cryptic manner during HAART. As such, a variety of approaches to both activate the latent reservoirs and deplete residual viral replication are being developed. In understanding the molecular pathogenesis of HIV-1 disease, one can potentially target these cellular reservoirs of HIV-1 persistence.