Cultural heritage assets monuments, historical buildings, landscapes are increasingly vulnerable to climate change-induced impacts. Southern European regions, including the Mediterranean basin, are particularly exposed to risks such as heatwaves, hygrothermal oscillations, flooding, wind, and seismicity. In Calabria, local geomorphological and socio-environmental fragilities further exacerbate the condition of minor historic centers. This chapter presents an advanced methodological framework for assessing climate change impacts on cultural heritage, with the goal of constructing a theoretical basis for a replicable and scalable climate vulnerability assessment tool. The framework connects environmental stressors with physical and biological deterioration pathways, extending its focus to the societal implications of heritage degradation. Based on established references, it identifies a coherent set of midpoint and endpoint indices to translate complex climate-heritage interactions into operational knowledge. The approach aims to guide strategic adaptation and co-design through digital and physical Living Labs, involving communities and institutions. While rooted in experimental evidence, the chapter focuses on methodological and modeling aspects, aiming to support innovative and adaptive strategies for the structural and environmental safety of heritage assets.