The goal of medication reconciliation is to prevent unintended medication discrepancies at times of transitions in care, which can lead to adverse events. Implementing effective medication reconciliation interventions has proven to be challenging. In this AHRQ-funded quality improvement study, five hospitals implemented a standardized approach to admission and discharge medication reconciliation using an evidence-based toolkit with longitudinal mentorship from the study investigators. The toolkit was implemented at each study site by a pharmacist and a hospitalist with support from local leadership. The intervention did not achieve overall reduction in potentially harmful medication discrepancies compared to baseline temporal trends. However, significant differences existed between the study sites, with sites that successfully implemented the recommended interventions being more likely to achieve reductions in harmful medication discrepancies. The study highlights the difficulty inherent in implementing quality improvement interventions in real-world settings. A WebM&M commentary discussed the importance of medication reconciliation and suggested best practices.