Tenofovir, a highly prescribed drug for the treatment of HIV/AIDS infections, has recently also shown its effectiveness as a potential topical microbicide drug in the prevention of HIV transmission. Here, we discuss the combination of tenofovir with various other antiretrovirals (ARV) highlighting the large class of carbohydrate-binding agents (CBAs) targeting the glycans on the viral envelope gp120 for their anti-HIV activity and their favorable combinatory potential. The tenofovir/CBA and several other ARV combinations consistently showed synergistic antiviral activities. Also combinations of other classes of ARV such as receptor (i.e. CD4, CXCR4 and CCR5) inhibitors, various monoclonal antibodies (mAbs) directed against the HIV envelope gp120 and HIV gp41 inhibitors were demonstrated to have synergistic anti-HIV effects. Moreover, certain antimetabolite drugs that show limited, if any, anti-HIV activity when administered as a single drug, can potentiate the antiviral activity of anti-HIV nucleoside analogues (NRTIs) by creating a beneficial metabolic and/or competitive advantage for the combined NRTIs. Thus, well-defined combinations of ARV may synergize and/or enhance the antiviral potency of the individual drugs and should be envisioned in the design of future microbicide studies. Recently, drugs such as tenofovir and acyclovir were demonstrated to be endowed with a dual (concomitant) antiviral (i.e. anti-HIV/HSV) activity in different in vitro, ex vivo and animal models. They also deserve special attention for their potential to prevent HIV transmission and to concomitantly suppress co-pathogens of HIV such as herpes viruses.