Nanostructures provide a programmable platform for precision imaging by integrating physical, chemical and biological functionalities within a single system. Switchable (OFF–ON) and biodegradable nanostructures are a transformative class of diagnostic agents with the potential to circulate silently and activate only within diseased tissue, while maintaining sufficient in vivo stability and predictable clearance. The combination of nanoscale design flexibility and biological recognition with temporal control enables these systems to overcome the poor selectivity and high background noise typical of conventional “always-on” probes. Their modular architectures allow them to be activated by tumor-associated triggers such as enzymatic dysregulation, metabolic shifts or immune dynamics, while ensuring they disassemble into fragments that are metabolically compatible and excretable. However, achieving this dual functionality demands a precise balance between in vivo stability, activation responsiveness and degradation kinetics. This tutorial review provides a mechanistic and translational overview of switchable and biodegradable nanostructures for cancer diagnostics, with an emphasis on current design strategies in the context of preclinical performance and translational constraints. We discuss how the physical principles of major imaging modalities guide specific design requirements and synthesize how key physicochemical parameters govern the balance between pharmacokinetics, activation, and degradation/clearance kinetics. Finally, we highlight emerging OFF–ON designs, including cascade amplification and logic-gated strategies, and discuss unresolved challenges in achieving consistent activation performance, sufficient stability and predictable clearance across different imaging scales, including single-cell and whole-body levels.