Adaptation to single and multiple stressors continues to be a priority across systems to address future changes and avoid adverse consequences.  However, adaptation efforts remain disparate across sectors. Such sector-specific approaches to adaptation are inherently limited reflecting the often coupled nature of systems – they interact to affect the inputs, constraints, and outcomes of each other. Research reported here demonstrates that failure to consider coupled systems in adaptation creates unrecognized tradeoffs, ineffective outcomes, or missed benefits of strategies. Holistic approaches to adaptation could help avoid negative consequences and realize benefits across systems and scales, but various constraints are associated with the effective deployment of such approaches in practice. For example, adaptation within the U.S. energy-water nexus (EWN) is hindered by a range of constraints, three of which are particularly pervasive: insufficient data and information, path dependence, and fragmented and disorganized institutions. Opportunities exist to overcome U.S.-EWN adaptation constraints. First, the availability and quality (collection, geolocation, methodologies) of relevant U.S.-EWN data requires improvement. Next, researchers and stakeholders should be able to access and analyze U.S.-EWN data alongside projections of decision-relevant systems and scales. Efforts should focus on creating and disseminating actionable information for decision-making that includes information on costs, benefits, and impacts on related systems. Prioritizing holistic adaptation now, before adaptation implementation is prevalent, increases the potential for synergistic actions and while avoiding unintended, adverse consequences in related systems.