The design of railroad tank cars is subject to structural and performance requirements and constrained by weight. They can be made safer by increasing tank thickness and adding various protective features, but these increase the weight and cost of the car and reduce its capacity and consequent transportation efficiency. Aircraft, automobiles and other vehicles are subject to a conceptually related set of problems and formal optimization techniques have been used to develop optimized design solutions using various objective functions. These general techniques can be adapted to solve a variety of tank car safety design optimization problems in which the tradeoff between safety and transportation efficiency is formally considered. Hazardous materials are substances or materials capable of posing an unreasonable risk to health, safety, and property when transported in commerce. However, within this broad, general definition, the hazard posed by these materials varies widely in terms of both the nature and magnitude of the hazard. Consequently, the benefit derived from measures intended to prevent hazardous material releases also varies considerably. Efficient allocation of safety resources requires quantitative understanding of the risks and benefits associated with different hazardous materials and various approaches to enhance safety. Addressing these questions in the context of railroad tank car safety design optimization is the principal focus of this dissertation. I develop a modeling approach in which tank car safety design optimization is considered as a two-phase process. The first phase addresses the tradeoff between safety and transportation efficiency by using Pareto optimization to identify the most efficient design combinations to improve safety while minimizing incremental weight. The second phase involves estimation of chemical-specific hazard levels and calculation of the consequent benefits and costs to determine the optimal level of protection for tank cars transporting different hazardous materials. This modeling approach is applied to two different current tank car safety design problems; consideration of tank car safety design enhancements to reduce the risk of transporting toxic inhalation hazard materials, and a group of chemicals that pose risk to the environment. The framework presented in this dissertation is can be used to assist industry and government policy makers to make better-informed decisions for safer transportation of hazardous materials. [The dissertation citations contained here are published with the permission of ProQuest LLC. Further reproduction is prohibited without permission. Copies of dissertations may be obtained by Telephone (800) 1-800-521-0600. Web page: http://www.proquest.com/en-US/products/dissertations/individuals.shtml.]