There is an urgent need to understand how animals will respond to ongoing anthropogenic change. Physiological data have been used to explore the proximate impacts of global change on organisms. If such descriptions of how organisms work are reasonable, then they might also provide reasonable predictions of the proximate responses of animals to changes in their environment. But such approaches ignore how fitness (co)varies with evolutionary drivers that are unrelated to physiology, and we know life does not work that way – shifts in the selective milieu induce evolutionary change, and organisms adapt such that their physiologies and life histories are altered. Here we attempt to link proximate and ultimate drivers of climate change responses by incorporating the size-dependence of physiological tolerances into a life-history optimisation model to predict how physiology will impact life-history evolution in the Anthropocene. Hypoxia tolerance generally improves as size increases within a species, while thermal tolerance decreases with size. Optimisation of the life history under size-dependent mortality results in dramatic decreases in optimum body size, generating a pattern consistent with size-mortality relationships in nature and offering a potential explanation for the widespread size declines observed during the Anthropocene.