Recent medical advancements have increased life expectancy, leading to a surge in patients affected by multiple chronic diseases and consequent polypharmacy, especially among older adults. This scenario increases the risk of drug interactions and adverse drug reactions, highlighting the need for medication review and deprescribing to reduce inappropriate medications and optimize therapeutic regimens, with the ultimate goal to improving patients’ health and quality of life. This position statement from the Italian Scientific Consortium on medication review and deprescribing aims to describe key elements, strategies, tools, timing, and healthcare professionals to be involved, for the implementation of medication review and deprescribing in different healthcare settings (i.e., primary care, hospital, long-term care facilities, and palliative care). Challenges and potential solutions for the implementation of medication review and deprescribing are also discussed.