jats:pPretreatment HIV drug resistance (PDR) has been increasing with scale-up of antiretroviral therapy (ART) in low- and middle-income countries. Delay in responding to rising levels of PDR is projected to fuel a worldwide increase in mortality, HIV incidence and ART costs. Strategies to curb the rise in PDR include using antiretrovirals (ARVs) with high-genetic barrier to resistance in first-line therapy and for prophylaxis in HIV exposed infants, enhancing HIV drug resistance surveillance in populations initiating, receiving ART, and in those on pre-exposure prophylaxis, universal access and effective use of viral-load tests, improving adherence and retention and minimizing ART programmatic quality gaps. In this review, we assess the drivers of PDR, and potential strategies to mitigate its rise in prevalence and impact in low- and middle-income countries.</jats:p>