The Mediterranean has been identified as a ‘climate change hot spot’, already experiencing faster warming rates than the global average, along with an increased occurrence of heat waves (HWs), prolonged droughts, and forest fires. During summer 2021, the Mediterranean faced prolonged and severe HWs, triggering hundreds of wildfires across the region. Greece, in particular, was hit by one of the most intense HWs in its modern history, with national all-time record temperatures being observed from 28 July to 6 August 2021. The HW was associated with extreme wildfires in many parts of the country, with catastrophic environmental and societal consequences. The study accentuated the rarity and special characteristics of this HW (HW2021) through the analysis of the historical climate record of the National Observatory of Athens (NOA) on a centennial time scale and comparison with previous HWs. The findings showed that HW2021 was ranked first in terms of persistence (with a total duration of 10 days) and highest observed nighttime temperatures, as well as ‘cumulative heat’, accounting for both the duration and intensity of the event. Exceptionally hot conditions during nighttime were intensified by the urban heat island effect in the city of Athens. Human exposure to heat-related stress during the event was further assessed by the use of bioclimatic indices such as the Universal Thermal Climate Index (UTCI). The study points to the interconnected climate risks in the area and especially to the increased exposure of urban populations to conditions of heat stress, due to the additive urban effect.