The highlands of Ethiopia are a densely populated, agriculturally active region characterized by strong topographic contrasts. These contrasts have significant implications for agricultural productivity and for vulnerability to climate variability and change. These differing vulnerabilities are evident in analyses of economic and health outcomes over time, and they were on stark display during the major El Niño drought of 2015. To provide meaningful analysis of climate vulnerability in this region and, ultimately, to support climate resilience strategies, it is necessary to account for this topographic diversity. Recognizing this, the Government of Ethiopia has applied an “adaptation zone” approach to climate change planning, in which adaptation zones are defined in large part by agroecology. Here, we present results of studies we have performed in the Ethiopian Highlands over the past decade in which agroecosystems were applied as a lens for analyzing hydrology, land management and change, agricultural production, and nutrition under climate variability. This approach has informed a number of active development initiatives in the region, including protection of high elevation zones, farmer-led initiatives on soil and water management, and introduction of new cropping strategies. Looking forward, climate projections at the scale of the agroecosystem point to emerging risks and opportunities for resilient agricultural development in the region.