The interior southwest United States is one of the hottest, driest regions on the planet, yet irrigated cropland agriculture is successfully practiced where there is access to surface water and/or groundwater. Through climate change, the southwest is projected to become even hotter and drier, increasing the challenges faced by farmers across the region. We can assess the vulnerability of cropland agriculture, to assist in developing potential solutions to these challenges of warming temperatures and water scarcity. However, these types of biophysical vulnerability assessment usually generate technological or policy-level solutions that do not necessarily account for farmers’ ability to respond to climate change impacts. Further, there are non-climatic factors that also threaten the future of agriculture in the region, such as population increase, loss of agricultural land, and increasing competition for depleting water resources. In this paper, we assert that to fully address how southwestern farmers may respond to climate change impacts, we must consider both biophysical outcome and contextual vulnerabilities. Future research on individual localities and/or specific commodities and including cross-disciplinary analysis of socio-economic, institutional, cultural, and political factors alongside biophysical factors will help to develop more substantive understanding of system vulnerabilities and feasible adaptive solutions.