With the breakdown of Dennard scaling, computer architects can no longer rely on integrated circuit energy efficiency to scale with transistor density, and must under-clock or power-gate parts of their designs in order to fit within given power budgets. Hardware accelerators may improve energy efficiency of some compute-intensive tasks, but as more tasks are accelerated, the general-purpose portions of workloads account for a larger share of execution time while also leaving less instruction, data, or task-level parallelism to exploit. Adaptive computing systems have potential to address these challenges by modifying their behavior at runtime. Adaptation requires runtime decision-making, which can be performed both in hardware and software. While software-based decision-making is more flexible and can execute higher complexity operations compared to hardware, it also incurs a significant latency and power overhead. Hardware designs are more limited in the space of decisions they can make, but have direct access to their own internal microarchitectural states and can make faster decisions, allowing for better-informed adaptation and extracting previously unobtainable performance and security benefits. In this dissertation I study (i) the viability and trade-offs of general-purpose adaptive systems, (ii) the difficulty and complexity of making adaptation decisions, and (iii) how time spent in the observation-analysis-adaptation cycle affects adaptation benefits. I introduce techniques for (a) modeling and understanding high performance computing systems and microarchitecture, (b) enabling hardware learning and decision-making through low-latency networks, and (c) on securing hardware designs using runtime decision-making. I propose an always-awake and active learning `hardware nervous system' pervasive throughout the chip that can reason about the individual hardware module performance, energy usage, and security. I present the design and implementation of (1) a reference architecture and (2) a microarchitecture-aware static binary instrumentation tool. Finally, I provide results showing (1) that runtime adaptation is a necessary to continue improving performance on general-purpose tasks, (2) that significant performance loss and performance variation happens under the ISA-level, and is unobservable without hardware support, and (3) that hardware must possess decision-making and ‘self-awareness’ capabilities at the microarchitecture level in order to efficiently use its own faculties.