Background <p>Vesicle-associated membrane proteins (VAMPs) are key regulators of membrane fusion, vesicular trafficking and intercellular communication. Structurally and functionally diverse, VAMPs participate in multiple physiological processes, and their dysfunction facilitates the progression of various aging-related diseases. This review aims to systematically summarize the molecular mechanisms and therapeutic potential of VAMPs.</p> Methods <p>We summarize current evidence to clarify the functions of VAMPs in aging-related disorders, and elaborate their roles in vesicle dynamic events as well as the regulatory effects of post-translational modifications on VAMP activity.</p> Results <p>VAMPs are closely involved in neurodegenerative, metabolic, cardiovascular diseases and cancers. They modulate the whole process of vesicle circulation, and post-translational modifications dynamically regulate VAMP function. VAMP-targeting agents present promising prospects for disease intervention.</p> Conclusion <p>Targeting VAMPs provides innovative therapeutic strategies to ameliorate aging-related pathological conditions.</p> Graphical Abstract <p></p>