The medicines retail sector is an essential element of many health systems in Africa and Asia, but it is also well known for poor practice. In the literature, it is recognised that improvements in the sector can only be made if more effective forms of governance and regulation can be identified. Recent debate suggests that interventions responsive to structural constraints that shape and underpin poor practice is a useful way forward. This paper presents data from a mixed-methods study conducted to explore regulation and the professional, economic and social constraints that shape rule breaking among drug shops in one district in Uganda. Our findings show that regulatory systems are undermined by frequent informal payments, and that although drug shops are often run by qualified staff, many are unlicensed and sell medicines beyond their legal permits. Most shops have either a small profit or a loss and rely on family and friends for additional resources as they compete in a highly saturated market. We argue that in the current context, drug shop vendors are survivalist entrepreneurs operating in a market in which it is extremely difficult to abide by policy, remain profitable and provide a service to the community. Structural changes in the medicines market, including removing unqualified sellers and making adjustments to policy are likely prerequisite if drug shops are to become places where individuals can earn a living, abide by the rules and facilitate access to medicines for people living in some of the world’s poorest countries.