The results of the application of an exergy-based method to highly dynamic, integrated hypersonic vehicle concepts are presented. Conventional aircraft systems and sub-systems traditionally are designed relying heavily on rules of thumb, individual experience, and rather simple, non-integrated tradeoff analyses, which are highly dependent on the evolutionary nature of vehicle development. In contrast, hypersonic vehicles may contain new sub-systems and revolutionary concepts for which there is no existing database to support an evolutionary synthesis/design approach. Thus, a simple tradeoff analysis becomes virtually impossible, particularly in light of the highly integrated, non-linear relationship between hypersonic vehicle sub-systems and the complexity of the missions involved. Therefore, the departure from existing databases and experience levels requires an integrated approach and a common metric for the synthesis/design of hypersonic vehicles to achieve an optimal synthesis/design. To that end, an exergy-based mission integrated methodology is introduced and compared to traditional measures (including a non-integrated approach) by applying these to the synthesis/design and operational optimization of a hypersonic vehicle configuration comprised of an airframe and a propulsion sub-system (consisting of inlet, combustor, and nozzle components). Results of these optimizations are presented and include a quantification of all vehicle losses in terms of exergy lost or destroyed, providing a common metric for the vehicle designer to identify where the largest improvements in vehicle performance can be made. Furthermore, via a number of parametric studies, the impacts of the design and operational decision variables on exergy destruction are discussed.