Emerging drug resistance and side effects complicate the clinical care of HIV-infected patients. Accumulating data from basic science and clinical studies suggest that hydroxyurea-based regimens are effective treatment options for patients at various stages of disease. Review of the clinical studies confirms that hydroxyurea-based regimens produce potent and sustained viral suppression, with an unexpected high degree of tolerability, in patients with primary and chronic HIV infection. Hydroxyurea, the first antiretroviral drug targeting a cellular factor, represents a novel and inexpensive approach to combination therapy for HIV infection. Hydroxyurea is not prone to resistance while impeding resistance to reverse transcriptase inhibitors. The cytostatic properties of hydroxyurea may contribute to its immunomodulatory effects while reducing activated HIV target cells. These characteristics make hydroxyurea a good candidate for long-term treatment of HIV infected individuals. Future studies including those that evaluate optimal dosing a long-term use will continue to define the role for this agent in the treatment of HIV infection.