Hazardous materials such as fuel, solvents, organic waste from hospitals, used batteries, explosives, and nuclear waste need to be transported to and from the facilities that use, produce, and dispose of them. Managing these transports requires a design that alleviates negative effects of these activities, such as the loss of lives, environmental damage, and the destruction of property. Despite the large body of literature addressing numerous aspects regarding hazardous materials, there is no clear consensus on how potential adverse effects should be measured when optimizing facility location and route design. Our analysis commences with a look at the primary stakeholders in these activities: the population that is potentially affected by transportation, the firms that pay for it, and the government regulator, whose task is to protect the population at large. This chapter proposes two new indicators related to these activities, which are easy to compute, avoid the use of unreliable very low probability estimations, take care of the regulatory agencies and public concern, and, in our view, are more understandable to the public. Mathematical programming problems that integrate criteria for all stakeholders are formulated and solved. The methodology is then applied to a real case in order to determine an optimal transport route for the transport of hazardous materials in and out of the city of Santiago, Chile.