The last decade has shown that networked cyber-physical systems (NCPS) are the future of critical infrastructure such as transportation systems and energy production. However, they have introduced an uncharted territory of security vulnerabilities and a wider attack surface, mainly due to network openness and the deeply integrated physical and cyber spaces. On the other hand, relying on manual analysis of intrusion detection alarms might be effective in stopping run-of-the-mill automated probes but remain useless against the growing number of targeted, persistent, and often AI-enabled attacks on large-scale NCPS. Hence, there is a pressing need for new research directions to provide advanced protection. This paper introduces a novel security paradigm for emerging NCPS, namely Autonomous Cyber-Physical Defense (ACPD). We lay out the theoretical foundations and describe the methods for building autonomous and stealthy cyber-physical defense agents that are able to dynamically hunt, detect, and respond to intelligent and sophisticated adversaries in real time without human intervention. By leveraging the power of game theory and multi-agent reinforcement learning, these self-learning agents will be able to deploy complex cyber-physical deception scenarios on the fly, generate optimal and adaptive security policies without prior knowledge of potential threats, and defend themselves against adversarial learning. Nonetheless, serious challenges including trustworthiness, scalability, and transfer learning are yet to be addressed for these autonomous agents to become the next-generation tools of cyber-physical defense.