Drought-induced tree mortality, including large-scale die-off events and increases in background rates of mortality, is a global phenomenon that can directly impact numerous earth system properties and ecosystem goods and services. Tree mortality is particularly of concern because of the likelihood that it will increase in frequency and extent with climate change. Recent plant science advances related to drought have focused on understanding the physiological mechanisms that not only affect plant growth and associated carbon metabolism, but also the more challenging issue of predicting plant mortality thresholds. Although some advances related to mechanisms of mortality have been made and have increased emphasis on interrelationships between carbon metabolism and plant hydraulics, notably few studies have specifically evaluated effects of increasing atmospheric demand for moisture on rates of tree death. In this opinion article we highlight the importance of considering the key risks of future large-scale tree die-off and other mortality events arising from increased VPD. Here we focus on mortality of trees, but our point about the importance of VPD is also relevant to other vascular plants.