For past years, we have been interested in dioxolane nucleosides as potential anti-HIV agents (Chu et al., 1991; Kim et. al., 1992; Kim et. al., 1993; Furman, et al., 2001; Chu, et al., 2005; Liang, et. al., 2006), which possess a dioxolane ring in place of a classical carbohydrate moiety in nucleosides. The dioxolane nucleosides, such as (-)-β-D-(2R,4R) 1,3-dioxolane 2,6-diamino purine (DAPD) and (-)-β-D-(2R,4R)-dioxolane-tymine (DOT), are interesting in that they demonstrated interesting anti-HIV activity against drug resistant mutants (Chong et al., 2002; Chong et al., 2004; Chu et al., 2005; Thompson et al., 2005) (Figure 1). DAPD (amdoxovir), a reverse transcriptase inhibitor (NRTI), is deaminated in vitro as well as in vivo, yields a metabolite, (-)-β-D-1,3-dioxolane guanosine (Gu et al., 1999). Both DAPD and DXG demonstrated potent in vitro anti-HIV activity against wild type as well drug resistant strains (such as AZT, 3TC and abacavir) (Furman et al., 2001). Preliminary in vitro studies of dioxolane nucleosides shown that the lack of cross-resistance to AZT and the reversal of AZT resistance by DXG resistance mutations provide strong rationales for the use of these compounds in combination with other agents (Bazmi et al., 2000; Gallant et al., 2003; Walmsley et al., 2003). In order to understand the mechanism of this antiviral activity, we have conducted molecular modeling studies, which revealed that the 1,3-dioxolane moiety plays a significant role in stabilizing the binding between the mutant HIV-1 RT and the nucleoside triphosphate (Chong et al., 2004; Chu et al., 2005).