In addressing adaptation and/or mitigation strategies in the Mediterranean region, a focus on achieving multiple goals across the water, energy, ecosystems and food sectors is imperative. Identifying synergies between these aspects is crucial to avoid negative outcomes and trade-offs. An integrated approach to the Water-Energy-Food-Ecosystem (WEFE) nexus is necessary, one which takes into account its interconnected nature and the potential for rebound effects from addressing individual aspects separately. Because of the region's temporal and spatial variabilities, dealing with the WEFE nexus requires transdisciplinary approaches that incorporate social, political, and governance aspects. In cases of high expected impacts from climate change, transformative adaptation involving significant changes in human inputs and system reorganisation becomes necessary, as incremental adaptations may reach their limits in effectiveness. Watershed management serves as an effective unit for managing the nexus, especially given the Mediterranean region's vulnerability to water stress. The complexity of the region's socio-economic and political diversity necessitates transboundary strategies in adaptation and mitigation efforts, alongside global agreements as a complement to the Paris Agreement. Evaluating adaptation and mitigation strategies in a context-specific manner is essential to ensure effectiveness. While digital and technological solutions, early warning tools, and climate services are valuable, they must be integrated with nature-based solutions, and broad societal understanding and engagement are vital. Despite being solutions, improvements in irrigation techniques can lead to unintended consequences on the WEFE nexus, such as increased water use through the expansion of irrigated surface area and intensity. Embracing behavioural changes, such as reducing meat consumption and food waste, and encouraging restrained consumption and sufficiency, holds high potential for both adaptation and mitigation in the face of environmental challenges.