It is a continual challenge trying to improve the quality of prescribing while concurrently trying to address increasing pharmaceutical development, utilization and expenditure. National and regional reforms and initiatives in Sweden have moderated growth in ambulatory drug expenditure to 2.7% per annum in recent years despite increasing volumes. National reforms include mandatory generic substitution and value-based pricing alongside devolution of drug budgets to the regions. Regional initiatives include strengthening the role of the regional Drug and Therapeutic Committees, further budget devolution as well as strategies incorporating prescribing guidance and monitoring coupled with financial incentives. The extent and nature of the regional initiatives vary depending on their characteristics. In this article, we compare initiatives undertaken in two major counties, Stockholm and Ostergötland, and their outcomes. Outcomes include annual drug budget savings while achieving agreed quality as well as increased adherence to prescribing targets and guidance; the latter associated with savings. Appraising these multifaceted reforms can provide guidance to other countries and regions in view of their diversity. Future steps must incorporate measures to improve the utilization of new expensive drugs, which should include horizon scanning and forecasting activities as well as post-launch activities involving monitoring of prescribing and registries. This may well require cooperation with other European countries.