Highly active antiretroviral therapy (HAART) can potently suppress human immunodeficiency virus (HIV) replication and prevent progression to AIDS. However, HAART does not cure infected patients. Instead, HIV persists in latently infected CD4+ T cells and various cryptic cellular reservoirs. Hence, under current therapy regimens, patients must continue taking HAART for the remainder of their lives. Eliminating residual replication-competent virus is critical if eradication of HIV is to be achieved. While this challenge is formidable, we describe here a number of innovative approaches intended to further deplete HIV in HAART-treated patients. New antiretroviral drugs that target different viral proteins and stages of the virus life cycle, compounds that enhance anti-HIV immune responses and novel gene therapy approaches may each play a role in improving long-term suppression of the virus. Moreover, methods for more specifically and efficiently inducing HIV from latency and eliminating the newly activated host cells are also under development.