BACKGROUND Despite dramatic increases in new drugs and regimens, a combination of two nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs) remains the backbone of many regimens to treat HIV. METHODS This article summarizes the pharmacokinetic characteristics of approved NRTIs that are currently in the international treatment and prevention guidelines. CONCLUSIONS Compared to other NRTIs, tenofovir alafenamide fumarate (TAF) is more advantageous in terms of potency and safety. It is therefore a preferred choice in combination with emtricitabine (FTC) in most HIV treatment guidelines. The efficacy of the two-drug combination of NRTI/Integrase strand-transfer inhibitor, i.e. lamivudine/dolutegravir has been approved as an option for initial therapy. This regimen however has some limitations in patients with HBV coinfection. The two NRTI combinations tenofovir disproxil fumarate (TDF)/FTC and TAF/FTC have also been approved for pre-exposure prophylaxis (PrEP). Interestingly, a promising long-acting nucleoside reverse transcriptase translocation inhibitor, islatravir, formulated for implant was well tolerated and remained effective for up to a year, suggesting its potential as a single agent for PrEP. In the next decade, it remains to be seen whether NRTI-based regimens will remain the backbone of preferred ART regimens, or if the treatment will eventually move toward NRTI-sparing regimens to avoid long-term NRTI-toxicity.