Options for antiretroviral therapy in patients infected with HIV continue to expand as new drugs are integrated into treatment regimens. Nucleoside/nucleotide reverse transcriptase inhibitors (Nt/NRTIs) remain the backbone of highly active antiretroviral therapy (HAART). Although this is the oldest class of antiretrovirals, pharmacokinetic and pharmacodynamic properties have been less studied as compare to protease inhibotors (PIs) and non-nucleoside reverse transcriptase inhibitors (NNRTIs). The aim of this article is to review the current status of clinical pharmacology onf Nt/NRTIs, highlighting the issues with clinical interest. Therefore, implications of intracellular pharmacokinetics on dosing schedule, potential for drug-drug interaction and pharmacodynamics is discussed.