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Accumulating evidence suggests that a global sense of meaning in life is related to physical health, including increased longevity and reduced morbidity. However, the mechanisms responsible for these relationships remain largely unknown and uninvestigated. Moreover, there is no unifying conceptual framework linking meaning in life to physical health. Our aims are to (a) review the literature linking meaning in life to potential mechanisms associated with better physical health; (b) offer a comprehensive conceptual framework associating meaning in life with physical health; and (c) introduce a new construct, meaning salience, as a potentially important intermediary mechanism. Specifically, we review the evidence suggesting that meaning in life is associated with reduced stress, more adaptive coping, and greater engagement in health-promoting behaviors. Our model proposes that effects of global sense of meaning are potentiated through increased meaning salience, or daily awareness of meaning in the moment, which enhances self-regulation. Suggestions are proposed for empirically examining this new model.