OBJECTIVES: Medicine shortages are a global phenomenon. A growing number of reports indicate the problem is increasingly affecting the European pharmaceutical market. The present study aims to investigate the characteristics, determinants, legal aspects and management of medicine shortages in Belgium, France and from the perspective of the European Union.  METHODS: A review of scientific and grey literature was performed. The legal framework on European and national level was reviewed. Primary qualitative data was collected through 22 semi-structured interviews with key representatives of health care systems’ stakeholders on the national and European level.  RESULTS: France reported three times more shortages than Belgium. However, the main therapy area, the major cause and the dynamics of medicine shortages were analogous between the two countries. Determinants of medicine shortages were categorised in manufacturing problems, distribution and supply issues, and economic-related challenges. Manufacturing problems were most frequently reported as the primary cause of medicine shortages. Laws and regulations related to medicine shortages are more extensive in France than Belgium. Several preventive and responsive measures were identified to address such shortages.  CONCLUSIONS: Although medicine shortages are country-specific, the underlying mechanisms of medicine shortages appear to be similar in Belgium and France. Economic aspects seem to play a central role in the phenomenon of medicine shortages, as it influences stakeholders’ business decisions. The impact of the legal framework around medicines on the occurrence of medicine shortages may be limited. Collaboration, communication and coordination are key to any effective approach to address medicine shortages.