The development and clinical use of chemotherapeutic agents for the treatment of persistent HIV-1 infection over the past decade has profoundly and favorably affected the course of HIV-1 disease for many infected individuals. Unfortunately, the long-term use of these therapies is complicated by unwanted metabolic side effects, by issues of adherence, and by the selection of viral variants with reduced susceptibility. These complications have spurred the search for new anti-HIV-1 agents having improved pharmacological properties and expressing activity against viral variants resistant to the currently available agents. This brief review describes the current state of this search as well as potentially novel viral targets for chemotherapeutic intervention.