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• Experimentation in Andalusia is affected by frequent extreme heat events and droughts. • Maximum temperatures above 32.5°C around heading reduced wheat yield. • Mild temperatures and severe water stress after heading increased protein. • Irrigation in heading and earlier sowing date mitigate the effects of climate change. • Extreme heat events can affect the effectiveness of irrigation as adaptation measure. Extreme weather events, lower precipitation and higher temperatures play a relevant role in the assessment of wheat yield and protein concentration under future weather conditions in Mediterranean environments. To explore this topic, a dataset of long-term wheat cultivar trials carried out in 17 locations in Andalusia, southern Spain, between 1990 and 2017, and covering a wide range of weather conditions, has been analyzed. The occurrence of maximum temperatures surpassing 32.5°C during heading showed significant correlations with yield, and generated reductions of up to 30% of the maximum observed yield. Similarly, water stress up to 20 days after heading or numerous days with both high temperatures and water stress up to 45 days after heading, also showed significant correlations with yield, and generated reductions of up to 23% and 41%, respectively. Moreover, irrigation showed a very relevant role, with the minimum relative yield increasing from 9% under rainfed conditions to 56% with irrigation supply higher than 150mm. For protein concentration, frequent joint events combining mild temperatures and severe water stresses around heading showed increases of 3 %-units. The future weather conditions projected for southern Spain will enhance risk of yield reduction and protein concentration increases, with a high spatial variability. Earlier sowing dates reduce the coincidence of extreme weather events with critical crop development stages, and thus the effects on yield and protein concentration, even identifying conditions that the impact was fully reversed. Similarly, irrigation during heading mitigated the negative effects of water stress on yield and the positive effects on protein concentration. The combination of long-term cultivar trials under semi-arid weather conditions, modeling and future climate projections constitutes an excellent tool for the assessment of vulnerable/suitable areas, and for the identification of site-specific adaptation measures to ensure the sustainability of wheat-growing areas in southern Europe. [ABSTRACT FROM AUTHOR]