Observation‐based and modeling studies have identified the Eastern Mediterranean and Middle East (EMME) region as a prominent climate change hotspot. While several initiatives have addressed the impacts of climate change in parts of the EMME, here we present an updated assessment, covering a wide range of timescales, phenomena and future pathways. Our assessment is based on a revised analysis of recent observations and projections and an extensive overview of the recent scientific literature on the causes and effects of regional climate change. Greenhouse gas emissions in the EMME are growing rapidly, surpassing those of the European Union, hence contributing significantly to climate change. Over the past half‐century and especially during recent decades, the EMME has warmed significantly faster than other inhabited regions. At the same time, changes in the hydrological cycle have become evident. The observed recent temperature increase of about 0.45°C per decade is projected to continue, although strong global greenhouse gas emission reductions could moderate this trend. In addition to projected changes in mean climate conditions, we call attention to extreme weather events with potentially disruptive societal impacts. These include the strongly increasing severity and duration of heatwaves, droughts and dust storms, as well as torrential rain events that can trigger flash floods. Our review is complemented by a discussion of atmospheric pollution and land‐use change in the region, including urbanization, desertification and forest fires. Finally, we identify sectors that may be critically affected and formulate adaptation and research recommendations toward greater resilience of the EMME region to climate change.