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Widespread resistance of Plasmodium falciparum parasites to commonly used antimalarials, such as chloroquine, has resulted in many endemic countries considering changing their malaria treatment policy. Identifying and understanding the key influences that affect decision-making, and factors that facilitate or undermine policy implementation, is critical for improving the policy process and guiding resource allocation during this process. A historical review of archival documents from Malaŵi and data obtained from in-depth policy studies in four countries (Tanzania, South Africa, Kenya and Peru) that have changed malaria treatment policy provides important lessons about decision-making, the policy cycle and complex policy environment, while specifically identifying strategies successfully employed to facilitate policy-making and implementation. Findings from these country-level studies indicate that the process of malaria drug policy review should be institutionalized in endemic countries and based on systematically collected data. Key stakeholders need to be identified early and engaged in the process, while improved communication is needed on all levels. Although malaria drug policy change is often perceived to be a daunting task, using these and other proven strategies should assist endemic countries to tackle this challenge in a systematic fashion that ensures the development and implementation of the rational malaria drug policy.