Establishment of highly active antiretroviral therapy (HAART) has brought about dramatic improvement of the prognosis of HIV-1 infection. On the other hand, several drawbacks associated with long-term HARRT have been demonstrated. Among them, emergence of drug-resistant viruses is a serious problem; therefore compounds with novel mechanisms of action have been investigated to overcome the problem. Novel reverse transcriptase inhibitors (RTIs) and protease inhibitors (PIs) recently approved for clinical use are effective against existing resistant strains by once daily administration. In addition, the virus entry (fusion) inhibitor has also been licensed. Since this compound targets a molecule other than reverse transcriptase and protease for inhibition of HIV-1 replication, it is active against HIV-1 highly resistant to RTIs and PIs. Furthermore, clinical trials with CCR 5 (coreceptor of HIV-1) antagonists are in progress, and inhibitors of integrase, HIV-1 gene expression, and virion assembly have been identified.