The highway infrastructure system in the United States is deteriorating and facing an increased number of threats from natural and man-made hazards, including earthquakes, scour, hurricanes, and vehicle collisions. At the same time, the reliable functioning of the highway system plays an important role in emergency response and recovery processes after disaster strikes. However, there are several inadequacies in current codes and associated practice for the design of bridges, as well as funding restrictions for their upkeep. Although recent changes in the seismic design of bridges have adopted displacement-based design approaches to promote adequate performance under seismic loads, the current design philosophy hinges upon a uniform hazard perspective without explicit consideration of a homogeneous risk of damage or collapse. In addition, this approach does not reflect the influence of individual bridges on the transportation network behaviour, which is desirable to estimate the performance of a transportation infrastructure system and enhance its overall post-event operation. Moreover, current bridge design specifications deal with various extreme hazards independent of one another. The reliable performance of transportation infrastructure systems under natural hazards requires a new life-cycle risk-based design method, along with effective resource assignment and prioritization strategies. This thesis will address these noted gaps by putting forward a risk consistent design approach for bridges and associated transportation networks. To enable the proposed shift toward risk-based design of bridges and transportation networks, this thesis develops a framework to evaluate the life-cycle risk (LCR) and life-cycle cost (LCC) of structures based on the time-dependent hazard function approach. The resulting LCR formulation provides a basis for inverse risk analyses to determine the design parameters required to achieve an acceptable risk level. A key advantage of this formulation relative to most existing methods is that it captures the change in structural vulnerability throughout a structure’s lifetime due to structural deterioration as well as changes in loading, while most previous studies neglect this feature assuming that the annual failure probability of a structure or an infrastructure system is constant during the design life. This methodology is also amenable to future extensions that include benefits and impacts to society. To incorporate the transportation infrastructure system level performance into the design and retrofit of bridges in practice, this thesis proposes a new bridge ranking method based on graph theoretic metrics that quantifies network topology features while also incorporating individual bridge characteristics, such as bridge vulnerability and construction cost. This methodology is flexible enough to include in the future socio-demographic factors (e.g., population density, median household income, and vote margin) that affect policy and the distribution of funds to top ranking bridges. Based on the bridge ranking results, an inverse reliability method is used to quantitatively determine the individual bridge reliability levels required to achieve a target performance for entire transportation networks—a new result bound to inform engineering practice. This top-down bridge design approach is superior to current structure-specific design methods because highway bridges are integral parts of entire transportation networks, which means that the design of new bridges or prioritization of existing bridges for upgrade based solely on their structural behavior is not appropriate. Bridge design must account for the topology of the transportation network and the desired system-level performance. Based on the required individual bridge reliability levels for the transportation network, a new method for displacement-based uniform risk design of bridges under seismic hazards considering the effect of soil-structure interaction is also put forward. The method is desirable in practice to reduce the uncertainty in the performance of bridges across regions. Furthermore, no risk-based combination of extreme events for the design of bridges is currently available. This thesis investigates the feasibility of establishing a risk-based design framework to address multiple extreme hazards, particularly scour and earthquake, because they are the most common reason of collapse of bridges in the United States. This risk-consistent multi-hazard bridge design framework provides a basis for combinations of earthquake and scour loads that is also consistent with the load and resistance factor design (LRFD) methodology that is widely used in practice. In addition to providing an LCR framework to the risk-based design of highway bridges and associated transportation networks, modeling complexities typically simplified or neglected in the risk assessment and design of bridges are explored in this thesis. For example, the influence of vertical ground motions as well as soil-structure interaction and liquefaction, which tend to be ignored in current bridge design approaches, are accounted for within the uniform risk framework and illustrated through the seismic risk assessment of a coupled bridge-soil-foundation system. The integrated, uniform, and risk-based framework proposed in this thesis has the potential to directly improve the safety and reliability of transportation infrastructure systems under deteriorating conditions and in the presence of natural hazards and limited funds in the United States. The findings of this thesis will benefit the department of transportation (DOT), AASHTO committee, and other agencies, such as offices of emergency management. The risk-consistent framework is desirable in practice to reduce the uncertainty in the performance of highway transportation system across regions under multiple natural hazards.