In the past years, a variety of 4'-C-substituted-2'-deoxynucleosides (4'SdNs) were designed, synthesized, and examined as potential therapeutics against human immunodeficiency virus (HIV) infection and certain such analogues proved to exert potent activity against HIV-1 in vitro. Unlike currently available nucleoside reverse transcriptase (RT) inhibitors such as 3'-azido-3'-deoxythymidine (AZT), which have the 2',3'-dideoxy configuration and thereby cause DNA chain termination in the elongating proviral DNA, 4'SdNs do retain the 3'-alpha-OH moiety but also appear to work against retrovirus as proviral DNA chain terminators. Several 4'SdNs have been shown to be active against various laboratory and clinical HIV-1 strains including known drug-resistant HIV-1 variants. Among such 4'SdNs is 4'-azido-2'-deoxythymidine (4'-AZT) which exerts potent antiviral activity against wild type and AZT-resistant clinical HIV strains. More anti-HIV 4'SdNs have recently been reported including 4'-ethynylthymidine, 4'-ethynyl-2'-deoxy-D-ribofuranosyl-2,6-diaminopurine (4'-E-dDAP), 4'-ethynyl-2'-deoxyguanosine (4'-E-dG) and 4'-ethynyl-2'-deoxyadenosine (4'-E-dA). The latter three analogues are highly potent against HIV-1 and HIV-2 with EC50 values ranging from 0.0003 to 0.01 microM and have favorable cytotoxicity profiles with selective index (SI) values ranging from 975 to 2600. These 4'-ethynyl-2'-deoxynucleosides also exert potent activity against all known drug-resistant HIV-1 variants including the multi-dideoxynucleoside-resistant HIV and the variants with the 6-base pair inserts. Some of these compounds have favorable pharmacological properties and further development as potential therapeutics against HIV-1 infection is warranted.