In this article, we pointed out that understanding the physiology of differential climate change effects on organisms is one of the many urgent challenges faced in ecology and evolutionary biology. We explore how physiological ecology can contribute to a holistic view of climate change impacts on organisms and ecosystems and their evolutionary responses. We suggest that theoretical and experimental efforts not only need to improve our understanding of thermal limits to organisms, but also to consider multiple stressors both on land and in the oceans. As an example, we discuss recent efforts to understand the effects of various global change drivers on aquatic ectotherms in the field that led to the development of the concept of oxygen and capacity limited thermal tolerance (OCLTT) as a framework integrating various drivers and linking organisational levels from ecosystem to organism, tissue, cell, and molecules. We suggest seven core objectives of a comprehensive research program comprising the interplay among physiological, ecological, and evolutionary approaches for both aquatic and terrestrial organisms. While studies of individual aspects are already underway in many laboratories worldwide, integration of these findings into conceptual frameworks is needed not only within one organism group such as animals but also across organism domains such as Archaea, Bacteria, and Eukarya. Indeed, development of unifying concepts is relevant for interpreting existing and future findings in a coherent way and for projecting the future ecological and evolutionary effects of climate change on functional biodiversity. We also suggest that OCLTT may in the end and from an evolutionary point of view, be able to explain the limited thermal tolerance of metazoans when compared to other organisms.