A fundamental assumption by the Institute of Medicine (IOM) is that evidence-based medicine (EBM) improves the effectiveness of medical diagnosis and treatment and, thus, the safety of patients. However, EBM remains controversial, especially its links to patient safety. This chapter addresses three research questions: (1) How does EBM contribute to patient safety? (2) How and why is EBM limited in improving patient safety? and (3) How can patient safety be maximized, given the limitations of EBM? Currently, EMB contributes to patient safety both by educating clinicians on the value and use of empirical evidence for medical practice and via large-scale initiatives to improve care processes. Attempts to apply EBM to individual patient care are limited, in part, because EMB relies on biostatisical and epidemiological reasoning to assess whether a screening, diagnostic, or treatment process produces desired health outcomes for a general population. Health care processes that are most amenable to EBM are those that can be standardized or routinized; non-routine processes, such as diagnosing and treating a person with both acute and chronic co-morbidities, are cases where EBM has limited applicability. To improve patient safety, health care organizations should not rely solely on EBM, but also recognize the need to foster mindfulness within the medical professions and develop patient-centric organizational systems and cultures. © 2008 Emerald Group Publishing Limited.