Purpose <p>Despite research efforts since the 1960s on ocular surface lubrication, a satisfactory explanation for how healthy ocular surfaces sustain tear film remains a mystery, and the lack of mechanical understanding hinders clinicians from designing effective treatments for ocular lubrication dysfunction-related diseases, including dry eye disease. This review aims to summarize the current understanding of ocular surface lubrication from molecular, mechanical, and homeostatic perspectives, highlight model systems and measurement techniques relevant for potential therapeutic developments, and discuss the challenges in translational research on the role of lubrication in ocular surface diseases.</p> Recent Findings <p>This review emphasized that the mechanical properties of the ocular surface, including its interfacial and rheological properties, dictate the tear film stability and the friction at the corneal/conjunctival interface. As a sustainable tear film and low friction are indictive of a lubricious ocular surface, this review suggests that the interfacial and rheological properties are potential diagnosis target. A review of macromolecules present on the ocular surface and their contributions to its lubrication revealed a complex interactome between glycoproteins, polysaccharides, and lipids, challenging the earlier effort to identify a single key molecule. Specifically, the spatial stratification of macromolecules enables a synergistic lubrication mechanism.</p> Summary <p>This review identifies mechanical properties of the ocular surface as a crucial focus for future diagnosis and therapeutic strategies in ocular surface diseases. Understanding the synergistic lubrication mode is essential for developing effective interventions for ocular surface dysfunctions.</p>