Human immunodeficiency virus type 1 (HIV-1) gene expression and transcription is an essential step in the viral life cycle, which is considered to be a possible target for inhibition of HIV-1 replication. Among the factors involved in this step, the cellular transcription factor nuclear factor (NF)-kappaB is the most potent inducer of HIV-1 gene expression, while the viral transactivator protein Tat seems to play a central role in sustaining a high level of HIV-1 replication. Another important mechanism of HIV-1 gene expression is the nuclear export control of viral mRNA conducted by the viral regulatory protein Rev. Various attempts have been undertaken to discover selective inhibitors of HIV-1 gene expression and transcription. Several small-molecule compounds were reported to inhibit Tat functions though blocking either the Tat/TAR RNA interaction or the kinase activity of cellular cofactors, such as cyclin T1/CDK9. In the case of Rev inhibitors, it appears to be more difficult to find them than Tat inhibitors, and only a few compounds have been identified as Rev inhibitors. However, the selectivity of these Tat and Rev inhibitors was not high enough to eliminate the cytotoxicity to the host cells. Since the signal transduction pathways leading to NF-kappaB activation are redox regulated, several antioxidants have been shown to block HIV-1 transcription. Although some of them have progressed into clinical trials in HIV-1-infected patients, the results were not conclusive. In addition, various compounds have been identified as inhibitors of HIV-1 gene expression and transcription, yet their precise mechanisms are still unknown.