Over the last years, Unmanned Aerial Vehicles (UAVs) have gradually become a more efficient alternative to manned aircraft, and at present, they are being deployed in a broad spectrum of both military as well as civilian missions. This has led to an unprecedented market expansion with new challenges for the aeronautical industry, and as a result, it has created a need to implement the latest design tools in order to achieve faster idea-to-market times and higher product performance. As a complex engineering product, UAVs are comprised of numerous sub-systems with intricate synergies and hidden dependencies. To this end, Multidisciplinary Design Optimization (MDO) is a method that can identify systems with better performance through the concurrent consideration of several engineering disciplines under a common framework. Nevertheless, there are still many limitations in MDO, and to this date, some of the most critical gaps can be found in the disciplinary modeling, in the analysis capabilities, and in the organizational integration of the method. As an aeronautical product, UAVs are also expected to work together with other systems and to perform in various operating environments. In this respect, System of Systems (SoS) models enable the exploration of design interactions in various missions, and hence, they allow decision makers to identify capabilities that are beyond those of each individual system. As expected, this significantly more complex formulation raises new challenges regarding the decomposition of the problem, while at the same time, it sets further requirements in terms of analyses and mission simulation. In this light, this thesis focuses on the design optimization of UAVs by enhancing the current MDO capabilities and by exploring the use of SoS models. Two literature reviews serve as the basis for identifying the gaps and trends in the field, and in turn, five case studies try to address them by proposing a set of expansions. On the whole, the problem is approached from a technical as well as an organizational point of view, and thus, this research aims to propose solutions that can lead to better performance and that are also meaningful to the Product Development Process (PDP). Having established the above foundation, this work delves firstly into MDO, and more specifically, it presents a framework that has been enhanced with further system models and analysis capabilities, efficient computing solutions, and data visualization tools. At a secondary level, this work addresses the topic of SoS, and in particular, it presents a multi-level decomposition strategy, multi-fidelity disciplinary models, and a mission simulation module. Overall, this thesis presents quantitative data which aim to illustrate the benefits of design optimization on the performance of UAVs, and it concludes with a qualitative assessment of the effects that the proposed methods and tools can have on both the PDP and the organization.