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Emtricitabine (FTC) and lamivudine (3TC), containing an oxathiolane ring with unnatural (−)-stereochemistry, are widely used nucleoside reverse transcriptase inhibitors (NRTIs) in anti-HIV therapy. Treatment with FTC or 3TC primarily selects for the HIV-1 RT M184V/I resistance mutations. Here we provide a comprehensive kinetic and structural basis for inhibiting HIV-1 RT by (−)-FTC-TP and (−)-3TC-TP and drug resistance by M184V. (−)-FTC-TP and (−)-3TC-TP have higher binding affinities (1/K_d) for wild-type RT but slower incorporation rates than dCTP. HIV-1 RT ternary crystal structures with (−)-FTC-TP and (−)-3TC-TP corroborate kinetic results demonstrating that their oxathiolane sulfur orients toward the DNA primer 3′-terminus and their triphosphate exists in two different binding conformations. M184V RT displays greater (>200-fold)K_dfor theL-nucleotides and moderately higher (>9-fold)K_dfor theD-isomers compared to dCTP. The M184V RT structure illustrates how the mutation repositions the oxathiolane of (−)-FTC-TP and shifts its triphosphate into a non-productive conformation.