Globally, 49% of deaths from traffic crashes occur among vulnerable road users, including pedestrians, bicyclists, and motorcyclists. Approximately, a quarter of those killed are motorcyclists. The authors carried out a systematic review of the literature to evaluate the effectiveness of interventions to prevent motorcycle crashes and the associated morbidity and mortality. The studies included in this review provide evidence for the effectiveness of helmet use, protective clothing, training, and penalties for alcohol consumption and speeding in preventing injury and death to motorcyclists. The use of helmets is effective, especially if it is universally required by law for drivers and passengers. Training to obtain a license also has positive effects but not when it is totally voluntary. There is limited but consistent evidence that strengthening laws for penalties related to alcohol consumption or speeding has an impact on risk. Traffic calming interventions could help reduce crashes in urban areas. In jurisdictions where there is limited regulation or adherence to effective measures, such as the use of helmets, efforts should be directed primarily at expanding such practices. In other areas, efforts can focus on approaches based on alternative effective measures or on more innovative interventions adapted to local conditions.