The recent growth of medicine sales online represents a major disruption to pharmacy markets, with COVID-19 encouraging this trend further. While e-pharmacy businesses were initially the preserve of high-income countries, in the past decade they have been growing rapidly in low-income and middle-income countries (LMICs). Public health concerns associated with e-pharmacy include the sale of prescription-only medicines without a prescription and the sale of substandard and falsified medicines. There are also non-health-related risks such as consumer fraud and lack of data privacy. However, e-pharmacy may also have the potential to improve access to medicines. Drawing on existing literature and a set of key informant interviews in Kenya, Nigeria and India, we examine the e-pharmacy regulatory systems in LMICs. None of the study countries had yet enacted a regulatory framework specific to e-pharmacy. Key regulatory challenges included the lack of consensus on regulatory models, lack of regulatory capacity, regulating sales across borders and risks of over-regulation. However, e-pharmacy also presents opportunities to enhance medicine regulation—through consolidation in the sector, and the traceability and transparency that online records offer. The regulatory process needs to be adapted to keep pace with this dynamic landscape and exploit these possibilities. This will require exploration of a range of innovative regulatory options, collaboration with larger, more compliant businesses, and engagement with global regulatory bodies. A key first step must be ensuring that national regulators are equipped with the necessary awareness and technical expertise to actively oversee this e-pharmacy activity.