Medical errors and adverse events are now recognized as major threats to both individual and public health worldwide. This review provides a broad perspective on major effective, established, or promising strategies to reduce medical errors and harm. Initiatives to improve safety can be conceptualized as a "safety onion" with layers of protection, depending on their degree of remove from the patient. Interventions discussed include those applied at the levels of the patient (patient engagement and disclosure), the caregiver (education, teamwork, and checklists), the local workplace (culture and workplace changes), and the system (information technology and incident reporting systems). Promising interventions include forcing functions, computerized prescriber order entry with decision support, checklists, standardized handoffs and simulation training. Many of the interventions described still lack strong evidence of benefit, but this should not hold back implementation. Rather, it should spur innovation accompanied by evaluation and publication to share the results.