The impacts of climate change on fires are expected to be highly variable spatially and temporally. In heavily anthropized landscapes, the great number of factors affecting fire regimes further limits our ability to predict future fire activity caused by climate. To address this, we develop a new framework for analysing regional changes in fire regimes from specific spatiotemporal patterns of fires and climate, so-called pyroclimates. We aim to test the trends of fire activity and climate (1973–2009) across the Mediterranean and mountain ecosystems of south-eastern France, and to define the spatial distribution of pyroclimates. Stepwise-PCA and cluster analyses reveal that three pyroclimates capture the spatiotemporal patterns associated with fire regime and climatic conditions. Trend tests indicate a high significant increase in spring temperature and fire weather severity for most of the study area. In contrast, a general decreasing pattern of fire activity is observed since the early 1990s, specifically during summer in historically burned regions. However, winter and spring fires are becoming more frequent and extensive in less fire-prone mountains. Cross-correlation analyses indicate that inter-annual variations in extreme fire weather and fire activity were highly correlated. However, the intensity of relationships is pyroclimate-dependent. Our findings reveal that fire-climate relationships changed rapidly over space and time, presumably according to regional changes in land-use and fire policy. Assessing pyroclimates offers new perspectives for fire management and policy by delineating homogeneous zones with respect to fire, climate and their recent trends, and by revealing geographic contrasts in the underlying fire drivers.