Purpose of Review With the expanded roll-out of antiretrovirals for treatment and prevention of HIV during the last decade, the emergence of HIV drug resistance (HIVDR) has become a growing challenge. This review provides an overview of the epidemiology and trajectory of HIVDR globally with an emphasis on pediatric and adolescent populations. Recent Findings HIVDR is associated with suboptimal virologic suppression and treatment failure, leading to an increased risk of HIV transmission to uninfected people and increased morbidity and mortality among people living with HIV. High rates of HIVDR to non-nucleoside reverse transcriptase inhibitors globally are expected to decline with the introduction of the integrase strand transfer inhibitors and long-acting combination regimens, while challenge remains for HIVDR to other classes of antiretroviral drugs. Summary We highlight several solutions including increased HIV viral load monitoring, expanded HIVDR surveillance, and adopting antiretroviral regimens with a high-resistance barrier to decrease HIVDR. Implementation studies and programmatic changes are needed to determine the best approach to prevent and combat the development of HIVDR.