RNA interference (RNAi) holds great promise as gene therapy approach against viral pathogens, including HIV-1. A specific anti-HIV-1 response can be induced via transfection of synthetic small interfering RNAs (siRNAs) or via intracellular transgene expression of short hairpin RNAs (shRNAs) or microRNAs (miRNAs). Both targeting of the viral mRNAs or the mRNAs for cellular co-factors that are required for viral replication have been shown successful in suppressing HIV-1 replication. However, like conventional mono-therapies, the use of a single anti-HIV-1 RNAi inducer results in the emergence of RNAi-escape mutants. To prevent viral escape, a combinatorial RNAi approach should be used in which multiple RNAi effectors against HIV-1 are simultaneously expressed. Although induced RNAi is able to trigger a robust and specific knockdown of virus replication, it is becoming apparent that RNAi therapeutics encounter difficulties concerning off-target effects, cellular toxicity and specific delivery to the right cells. This review covers the recent progress in combinatorial RNAi-based approaches against HIV-1 using lentiviral vectors as a delivery system. The potential for a clinical gene therapy application will be discussed.