This review is devoted to self-healing materials (SHM) containing polyhedral oligomeric silsesquioxanes (POSS) as building blocks. The synthetic approach can vary depending on the role POSS are expected to play in a given system. POSS (especially double-decker silsesquioxanes) can be grafted in side chains of a polymer backbone or used as segments of the main chain. Appropriate functionalization allows the formation of dynamic bonds with POSS molecules and makes them an active component of SHM, both as crosslinking agents and as factors that enhance the dynamics of macromolecules in the polymer matrix. The latter effect can be achieved by reversible release of bulky POSS cages or by the formation of separated inclusions in the polymer matrix through hydrophobic interactions and POSS aggregation. The unique properties of POSS-based self-healing systems make them interesting and versatile materials for various applications (e.g., repairable coatings, sealants, sensors, soft materials for tissue engineering, drug delivery, and wound healing).