R2U2 (Realizable, Responsive, Unobtrusive Unit) is an extensible framework for runtime System Health Management (SHM) of cyber-physical systems. R2U2 can be run in hardware (e.g., FPGAs), or software; can monitor hardware, software, or a combination of the two; and can analyze a range of different types of system requirements during runtime. An R2U2 requirement is specified utilizing a hierarchical combination of building blocks: temporal formula runtime observers (in LTL or MTL), Bayesian networks, sensor filters, and Boolean testers. Importantly, the framework is extensible; it is designed to enable definitions of new building blocks in combination with the core structure. Originally deployed on Unmanned Aerial Systems (UAS), R2U2 is designed to run on a wide range of embedded platforms, from autonomous systems like rovers, satellites, and robots, to human-assistive ground systems and cockpits.R2U2 is named after the requirements it satisfies; while the exact requirements vary by platform and mission, the ability to formally reason about Realizability, Responsiveness, and Unobtrusiveness is necessary for flight certifiability, safety-critical system assurance, and achievement of technology readiness levels for target systems. Realizability ensures that R2U2 is sufficiently expressive to encapsulate meaningful runtime requirements while maintaining adaptability to run on different platforms, transition between different mission stages, and update quickly between missions. Responsiveness entails continuously monitoring the system under test, real-time reasoning, reporting intermediate status, and as-early-as-possible requirements evaluations. Unobtrusiveness ensures compliance with the crucial properties of the target architecture: