Road deaths are forecast to double by 2020, with the burden falling most heavily on low- and middle-income countries and, within those countries, on the most vulnerable and poorest road users. Half of the 1.2 million people killed and 50 million injured in road crashes each year are pedestrians, motorcyclists, bicyclists, and users of unsafe public transport; and more than 90 percent are from low- and middle-income countries. Because these are the areas where rapid motorization is taking place, the issue of safety in increasingly multi-modal environments is now of critical importance, particularly for pedestrians and bicyclists, since as vulnerable road users (VRU), they comprise a large proportion of injuries and deaths, and similar strategies for prevention of injuries and fatalities for these two groups are available. Although a great deal of additional research is needed to determine the costs and benefits of various proposed solutions, some basic principles can be identified to guide roadway and infrastructure design for improved pedestrian and bicyclist safety. The three broad but separate strategies for reducing the probability of an injury or fatality are: (i) reducing exposure, (ii) reducing the probability of a collision given exposure, and (iii) reducing the probability of injury given a collision. The purpose of this paper is to describe and illustrate these principles, discuss issues related to each one, and discuss the benefits—indeed, imperativeness—of the application of these principles by planners and traffic engineers.