In 12 years since the seminal AHRQ Making Health Care Safer report was issued, research in the patient safety field has grown considerably, yielding a much stronger evidence base for preventing some types of errors. However, the literature also shows examples of many interventions that were strongly touted initially, but whose early successes could not be replicated. The systematic reviews in this special supplement—released in conjunction with the new AHRQ report, Making Health Care Safer II, from which these reviews are derived—critically examine the evidence supporting 10 patient safety practices, including methods to prevent particularly common adverse events such as diagnostic errors, adverse events after hospital discharge, and medication errors. Even after a decade of research into patient safety strategies, relatively few strategies are strongly supported by evidence. Thus, this supplement highlights "the continuing tension between needing to improve care and knowing how to do it." By explicitly considering the role of intervention cost, ease of implementation, and the effect of context on intervention success, the reviews attempt to help policymakers and safety professionals make decisions around how to improve safety in the face of limited or equivocal evidence.