Hospitals began paying financial penalties for high-risk–adjusted 30-day readmission rates for certain diagnoses in October 2012. Physician leaders seeking to reduce readmission rates will find that proven interventions often require substantial up-front financial and organizational investment. To reduce readmissions while minimizing the investment, leaders need to develop new and creative strategies guided by the evidence. This article describes 5 proposed strategies or “best practices” derived from critical evaluation of prior interventions and experience in the field. These practices include matching the intensity of the intervention to the patient's risk of readmission, avoiding commonly used but unproven interventions, using interventions with a durable effect, creating an effective team before selecting an intervention, and focusing on previously unrecognized high-risk patient groups.