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Emergence of drug resistant strains of human immunodeficiency virus type 1 (HIV-1) is a major hindrance in the long-term treatment of HIV-1 infected individuals. Alternative strategies, including those directed to structural elements of viral targets, are needed to combat the growing acquired immune deficiency syndrome (AIDS) pandemic. The HIV-1 reverse transcriptase (RT) dimer interface, critical for dimer stability and catalytic function, is a novel target for designing new anti-HIV-1 drugs. Several existing RT inhibitors are known to impair polymerase function by destabilizing RT dimer stability and can serve as useful leads in this direction. Conversely, studies have shown that potent nonnucleoside reverse transcriptase inhibitors (NNRTIs) can enhance RT subunit interaction, which may contribute in part to the inhibitory effect of these drugs. Interface peptides are reported to suppress enzyme activity by interfering with active RT heterodimer formation. This review focuses on small molecule and peptide inhibitors that interfere with the formation of the active RT heterodimer and also discusses regions in the RT that are critical for RT dimerization that can be considered as potential targets for chemotherapeutic intervention.