The Millennium Ecosystem Assessment (MA) has identified climate change, habitat destruction, invasive species, overexploitation and pollution as the major drivers of biodiversity loss and sources of concern for human well-being. Understanding how these drivers operate and interact and how they might be mitigated are among the most pressing questions facing humanity. Here, we show how macrophysiology--the investigation of variation in physiological traits over large geographical, temporal and phylogenetic scales--can contribute significantly to answering these questions. We do so by demonstrating, for each of the MA drivers, how a macrophysiological approach can or has helped elucidate the impacts of these drivers and their interactions. Moreover, we illustrate that a large-scale physiological perspective can provide insights into previously unrecognized threats to diversity, such as the erosion of physiological variation and stress tolerance, which are a consequence of the removal of large species and individuals from the biosphere. In so doing we demonstrate that environmental physiologists have much to offer the scientific quest to resolve major environmental problems.