High-performance computing (HPC) has played an increasingly important role in the fields of research, commerce, and national security. Though HPC systems may inherit security issues from general-purpose computers, simply retrofitting traditional security mechanisms for HPC systems is inappropriate or ineffective. In this chapter, we provide an overview of the design and architecture of HPC systems, and analyze the potential threats and vulnerabilities in HPC systems. We also analyze how to use defense mechanisms from the aspects of implementation, methodology, application, and performance for autonomous cyber defense in HPC systems. This chapter provides a comprehensive review of autonomous security mechanisms for HPC security and sheds light on applying security defense mechanisms to HPC systems.