The increasing reliance on computer and communication technologies exposes control systems to cybersecurity threats. The physical systems can now be attacked through cyberspace. Emerging sophisticated attacks can exploit zero-day vulnerabilities, persist in the system for long periods of time, and advance stealthily to achieve their attack goals. Protection and prevention against such attacks are not always possible, and a paradigm shift to emphasize the resilience of a control system is the overarching objective for safeguarding control systems to protect the nation’s critical infrastructures. This book has developed a set of powerful and versatile tools to establish scientific co-design principles for integrating cyber and physical systems in a holistic manner. The methodologies in this project provide a holistic and interdisciplinary approach to the secure and resilient CPS design, bridging the gap between multiple disciplines such as computer science, control, communications, and economics. In this chapter, we present several problems that could be addressed by applying or extending the proposed methodologies, and discuss future research directions of the secure and resilient CPSs. We first present two attack models for CPSs, including the man-in-the-middle (MITM) attack and the compromised-key attacks. The cross-layer co-design framework can potentially address these two attack models. Most of the existing works have focused on data confidentiality and integrity. We argue that data availability plays a critical role in time-critical CPSs. There is a need to use the cross-layer design framework to design safe-mode mechanisms and defense strategies to improve data availability.