Medication safety in ambulatory care settings is an area of growing concern. This article describes ACTMed (ACTivating primary care for MEDicine safety), a cluster randomized trial set in Australia which intends to improve medication safety in primary care settings. The ACTMed intervention will use health information technology (e.g., clinical indicator algorithms), guideline-based clinical recommendations, shared decision-making, and financial incentives to reduce serious medication-related harm, medication-related hospitalizations, and death.