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The U.S. healthcare system is very complex and inundated with many challenges, ranging from escalating healthcare expenditure to increasing prevalence of medication errors. Emphasis on cost reduction and prevention of medication errors has given impetus to the development of computerized information technologies. Advanced technological innovation such as e-prescribing has the potential to improve quality of care, reduce costs and enhance patient satisfaction. Reaping these benefits is dependent on successful diffusion of innovation. This chapter summarizes the current literature covering diffusion of e-prescribing technology with an emphasis on the barriers and facilitators, and strategies to overcome these potential barriers.