According to an editorial, the introduction of dolutegravir in many low-income and middle-income countries (LMICs) offers great potential for improved outcomes and tolerability at a lower cost. However, data from this and other studies raise several important unanswered questions about the risks of emerging dolutegravir resistance in LMICs, particularly as many are transitioning millions of patients to first-line dolutegravir-based antiretroviral therapy (ART). It warns that if more people develop integrase resistance over time, there is the possibility that the role of dolutegravir in second-line therapy becomes less relevant. Furthermore, there is the additional limitation that dolutegravir is not yet considered safe for young children and women of childbearing age without access to contraception, which are a majority of patients in many LMICs. It calls on routine ART programmes to monitor emerging dolutegravir resistance and to quantify its clinical effects and potential for transmission.