Therapeutic strategies designed to treat HIV infection with combinations of antiviral drugs have proven to be the best approach for slowing the progression to AIDS. Despite the great success of highly active antiretroviral therapy (HAART), drug resistance and toxicity issues still remain a concern for some individuals. Therefore, alternative therapeutic strategies need to be developed to overcome these limitations. Nucleic acid-based therapeutics have been considered as an alternative to the currently used antivirals. In this regard, RNA interference (RNAi) can function as a gene-specific therapeutic option for controlling HIV-1 replication. Another type of therapeutic nucleic acid - aptamers - shows promise as a new and potent class of anti-HIV agent and can additionally function as a cell-type-specific delivery vehicle for targeted RNAi. The combined use of small interfering RNA (siRNAs) and aptamers could effectively block viral replication and prevent the emergence of resistant variants. In this review, we recapitulate recent progress and the therapeutic potential of aptamer-siRNA conjugates in the treatment of HIV infection.