Climate change, land degradation and drought affect millions of people living in drylands worldwide. With its food security depending almost entirely on irrigated agriculture, Central Asia is one of the arid regions highly vulnerable to water scarcity. Previous research of land and water use in the region has focused on improving water-use efficiency, soil management and identifying technical, institutional and agricultural innovations. However, vulnerability to climate change has rarely been considered, in spite of the imminent risks due to a higher-than-average warming perspective and the predicted melting of glaciers, which will greatly affect the availability of irrigation water. Using the Khorezm region in the irrigated lowlands of northwest Uzbekistan as an example, we identify the local patterns of vulnerability to climate variability and extremes. We look at on-going environmental degradation, water-use inefficiency, and barriers to climate change adaptation and mitigation, and based on an extensive review of research evidence from the region, we present concrete examples of initiatives for building resilience and improving climate risk management. These include improving water use efficiency and changing the cropping patterns that have a high potential to decrease the exposure and sensitivity of rural communities to climate risks. In addition, changes in land use such as the afforestation of degraded croplands, and introducing resource-smart cultivation practices such as conservation agriculture, may strengthen the capacity of farmers and institutions to respond to climate challenges. As these can be out-scaled to similar environments, i.e. the irrigated cotton and wheat growing lowland regions in Central Asia and the Caucasus, these findings may be relevant for regions beyond the immediate geographic area from which it draws its examples.