The clinical utility of intervention in HIV-1 disease has been proven by inhibitors targeting reverse transcriptase and protease. However, novel approaches including inhibition of viral entry, integration and assembly would provide additional options to maintain long-term suppression. The identification of specific inhibitors for each of these processes has recently validated these approaches as viable alternatives for the development of new agents to treat HIV-1 infection. The most recent preclinical advances in novel antiretroviral agents are reviewed and promising new approaches that target viral processes are highlighted.