Projections of greater interannual and intrannual climate variability, including increasing temperatures, longer and more intense drought periods, and more extreme precipitation events, present growing challenges for agricultural production in the Southern Plains of the USA. We assess agricultural vulnerabilities within this region to support identification and development of adaptation strategies at regional to local scales, where many management decisions are made. Exposure to the synergistic effects of warming, such as fewer and more intense precipitation events and greater overall weather variability, will uniquely affect rain-fed and irrigated cropping, high-value specialty crops, extensive and intensive livestock production, and forestry. Although the sensitivities of various agricultural sectors to climatic stressors can be difficult to identify at regional scales, we summarize that crops irrigated from the Ogallala aquifer possess a high sensitivity; rangeland beef cattle production a low sensitivity; and rain-fed crops, forestry, and specialty crops intermediate sensitivities. Numerous adaptation strategies have been identified, including drought contingency planning, increased soil health, improved forecasts and associated decision support tools, and implementation of policies and financial instruments for risk management. However, the extent to which these strategies are adopted is variable and influenced by both biophysical and socioeconomic considerations. Inadequate local-and regional-scale climate risk and resilience information suggests that climate vulnerability research and climate adaptation approaches need to include bottom-up approaches such as learning networks and peer-to-peer communication.