Bioorthogonal reactions play a key role in controlled chemical transformations in living systems and are therefore applied to a diverse area of biological and medical applications. However, these applications can be limited by poor selectivity, slow kinetics under biological conditions, and intrinsic incompatibility between the introduced materials and the cellular environment. An emerging strategy for greater functional control over bioorthogonal transformations is the employment of supramolecular strategies or constructs. Herein, we focus on synthetic supramolecular systems that (i) improve biocompatibility by shielding reactive species within protective supramolecular constructs from harsh biological environments; (ii) allow for integration of subcellular targeting moieties; (iii) reduce toxicity; (iv) accelerate reaction rates through molecular preorganization; (v) explore entirely new tools, such as catalysis regulated by controlled stimuli at a functionalized surface. Through rational integration of these supramolecular strategies, bioorthogonal reactions could achieve enhanced precision, faster kinetics, and targeted reactivity within specific tissues, cells, or organelles, subsequently paving the way for further applications in chemical biology and therapeutic interventions.