Polypharmacy is growing in Canada, along with adverse drug events and drug-related costs. Part of the solution may be deprescribing, the planned and supervised process of dose reduction or stopping of medications that may be causing harm or are no longer providing benefit. Deprescribing can be a complex process, involving the intersection of patients, health care providers, and organizational and policy factors serving as enablers or barriers. This article describes the justification, theoretical foundation, and process for developing a Canadian Deprescribing Network (CaDeN), a network of individuals, organizations, and decision-makers committed to promoting the appropriate use of medications and non-pharmacological approaches to care, especially among older people in Canada. CaDeN will deploy multiple levels of action across multiple stakeholder groups simultaneously in an ecological approach to health system change. CaDeN proposes a unique model that might be applied both in national settings and for different transformational challenges in health care.