Most health system strengthening interventions ignore interconnections between systems components. In particular, complex relationships between medicines and health financing, human resources, health information and service delivery are not given sufficient consideration. As a consequence, populations' access to medicines (ATM) is addressed mainly through fragmented, often vertical approaches usually focusing on supply, unrelated to the wider issue of access to health services and interventions. The objective of this article is to embed ATM in a health system perspective. For this purpose, we perform a structured literature review: we examine existing ATM frameworks, review determinants of ATM and define at which level of the health system they are likely to occur; we analyse to which extent existing ATM frameworks take into account access constraints at different levels of the health system. Our findings suggest that ATM barriers are complex and interconnected as they occur at multiple levels of the health system. Existing ATM frameworks only partially address the full range of ATM barriers. We propose three essential paradigm shifts that take into account complex and dynamic relationships between medicines and other components of the health system. A holistic view of demand-side constraints in tandem with consideration of multiple and dynamic relationships between medicines and other health system resources should be applied; it should be recognized that determinants of ATM are rooted in national, regional and international contexts. These are schematized in a new framework proposing a health system perspective on ATM.