The Klamath-Siskiyou Ecoregion has been a refuge for species during past climate change events, but current anthropogenic stressors are likely compromising its effectiveness as a refugium for this century's projected changes. Reducing non-climate stressors and securing protection for large, complex landscapes are important long-term actions to alleviate climate change impacts on biodiversity. Equally important is the immediate protection of a network of climate change microrefugia, particularly old growth and intact forests on north-facing slopes and in canyon bottoms, lower- and middle-elevations, wetter coastal mountains, and along elevational gradients. Such areas provide local opportunities for vulnerable species to persist within the ecoregion. We identify a provisional set of 22 highest-priority and 40 high-priority microrefugia that occur mostly outside of existing protected areas and along wetter and lower elevations of the ecoregion. Proposed reserve designs, if fully implemented, would capture most of the recommended microrefugia, although we found 11 important gaps. Most of the region's biodiversity, endemic species, and species vulnerable to climate change are invertebrates, non-vascular plants, and fungi that are largely restricted to persistently cool and moist late-successional forests. Opportunities for climate change response for vulnerable taxa will necessarily be local due to a limited capacity of many species to move to new habitat, even over relatively small distances where land use practices create inhospitable conditions. The ecoregion's distinctive and endemic serpentine-substrate flora also is at risk and possible refugia are sites that will retain wet soil conditions, such as seeps and bogs.