Safe and effective pharmacological treatment remains one of the greatest challenges in medicine, where models of healthcare delivery lag behind the enormous growth in single disease focused treatment with medicines. The implications for safe, efficient, and effective deployment of healthcare resources and sustainability are significant from both healthcare and societal perspectives. This chapter will highlight the importance of addressing the public health issue of polypharmacy as part of an integrated approach to patient care and its impact on patient safety. It will describe a seven-step process for systematic review of appropriateness of patient’s medication with multiple morbidities, which is patient centered and encourages the patient to be part of the decision-making.