<p>Silsesquioxanes (SQs) represent a unique class of hybrid materials combining the nature of an inorganic Si–O–Si cage core with organic functional groups, enabling precise structural design at the molecular level. Their well-defined 3D nanoscale architecture, and tunable functionality make them attractive building blocks for advanced materials with applications in fields ranging from polymer science and catalysis to electronics and biomedicine. Nevertheless, the efficient and selective functionalization of SQs remains a significant synthetic challenge, primarily due to steric constraints and the limited scope of conventional modification strategies. Click chemistry has emerged as one of the most powerful approaches for overcoming these limitations by providing highly efficient, selective, and modular transformations. This review critically evaluates recent advances in the application of click chemistry to silsesquioxane functionalization. Particular attention is devoted to the preparation of “clickable” SQ precursors and to single-, double-, and multi-click strategies employing reactions such as CuAAC, SPAAC, Thiol-Ene, Diels–Alder, oxime ligation, and Menshutkin quaternization. Rather than providing a descriptive overview, this review critically compares the efficiency, scope, and limitations of individual click methodologies in the context of silsesquioxane chemistry, identifying promising directions for future developments. The review highlights how click chemistry enables the rational design of mono- and multifunctional SQ architectures for diverse applications, including polymeric and hybrid materials, self-healing systems, hydrogels, porous materials, surfactants, and biomedical platforms. Overall, it provides a comprehensive perspective on the evolving role of click chemistry in silsesquioxane chemistry and advanced hybrid material design.</p> Graphical Abstract <p></p>