Background <p>The precision delivery of active pharmaceutical ingredients remains a major challenge in modern pharmacology, where conventional therapies often lack selectivity and cause severe side effects. Stimuli-responsive drug delivery systems (SRDDS) represent a promising strategy to achieve controlled release in response to pathological microenvironments or external triggers. While various organic and inorganic carriers have been investigated, cyclodextrins (CDs) occupy a unique position due to their biocompatibility, safety record, and distinctive molecular architecture. Beyond their established role as solubilizing excipients, CDs can act as a fundamental component capable of driving responsiveness within drug delivery systems.</p> Objective <p>This review highlights cyclodextrin-based stimuli-responsive systems (SRCDS) in which CDs themselves mediate responsiveness, rather than serving as simple structural elements.</p> Scope and Focus <p>A comparative discussion of different responsive mechanisms is provided, offering insights into the design principles that may accelerate the clinical translation of CD-based SRDDS. A particular focus will be provided to chemical structure components exerting stimuli responsiveness. In addition, recent publications on SRCDS with pharmacological or biological experimental investigations and relevance are reviewed, with particular attention to applications in cancer therapy.</p> Graphical Abstract <p></p>