Global climate change threatens global biodiversity, ecosystem function, and human wellbeing, with thousands of publications demonstrating impacts across a wide diversity of taxonomic groups, ecosystems, economics, and social structure. A review by Hughes [1] identified many of the ways that organisms may be affected by and/ or respond to climate change. Since then, there has been a dramatic increase in the number of case studies attesting to ecological impacts [2], prompting several recent reviews on the subject (e.g., [3–6]). Several global meta-analyses confirm the pervasiveness of the global climate change “fingerprint” across continents, ecosystems, processes, and species [7–9]. Some studies have predicted increasingly severe future impacts with potentially high extinction rates in natural systems around the world [10,11]. Responding to this threat will require a concerted, multi-disciplinary, multi-scale, multi-taxon research effort that improves our predictive capacity to identify and prioritise vulnerable species in order to inform governments of the seriousness of the threat and to facilitate conservation adaptation and management [12,13]. If we are to minimise global biodiversity loss, we need significant decreases in global emissions to be combined with environmental management that is guided by sensible prioritisation of relative vulnerability. That is, we need to determine which species, habitats, and ecosystems will be most vulnerable, exactly what aspects of their ecological and evolutionary biology determine their vulnerability, and what we can do about managing this vulnerability and minimising the realised impacts. There is an emerging literature on specific traits that promote vulnerability under climate change (e.g., thermal tolerance [14]) as well as a broad literature on the traits that influence species’ vulnerability generally (e.g., review by [15]). Less is known about the various mechanisms for either ecological or evolutionary adaptation to climate change, although it is increasingly recognised as a vital component of assessing vulnerability [16,17]. Despite this emerging pool of knowledge, we believe that progress in vulnerability assessment relating to climate change could be hastened if a unified framework was available to coordinate the activities of disparate research disciplines. Specifically, what is needed is a complete working framework for assessing the vulnerability of species that explicitly links: the various components of biotic vulnerability; the regional and local factors determining exposure to climatic change; the potential for both evolutionary and ecological responses, resilience, and active management to mediate the final realised impacts; and the potential for feedback effects. Such a framework would be invaluable as it would integrate and guide thought, research programmes, and policy in the biodiversity/climate change arena and allow significant gaps in knowledge to be clearly identified. To this end, we present a conceptual framework that addresses these challenges (Figure 1). Vulnerability is the susceptibility of a system to a negative impact [18]. A practical first step in assessing vulnerability is to differentiate between factors that determine exposure and factors that govern sensitivity [19,20]. In this context, sensitivity is considered to be governed by traits that are intrinsic to a species and by exposure to factors that are extrinsic to the species and determined by regional climate change and local habitat effects.