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Wine production and quality are highly sensitive to local weather variability and climatic conditions. To assess these characteristics, this research examines high-resolution bioclimatic zoning over 50 protected denominations of origin (DOs)/sub-regions in mainland Portugal through the analysis of two selected bioclimatic indices (dryness and Huglin indices). The analysis is based on a new very high-resolution dataset over mainland Portugal and for a baseline period (1981-2015). Climate change projections are also assessed for two scenarios (RCP4.5 and RCP8.5) and using a 5-member climate model ensemble over the future periods of 2041-2070 and 2071-2100. A principal component analysis was applied to the time mean spatial patterns of the two selected bioclimatic indices, for the baseline period (1981-2015) and only over the planted vineyard cover areas in each region, isolating a new optimized combined index which was used for subsequent analysis. The results for the present conditions highlight the spatial variability of Portuguese DO/sub-regions. This study also shows that for the future periods, and regardless of the scenario, the wine sector in Portugal will likely see important bioclimatic changes across most DOs. Increases in the growing-season mean temperatures in all the Portuguese winemaking DO/sub-regions, accompanied by increasing severe dryness, are projected in future climates, mainly in south-eastern Portugal and along the upper Douro Valley (Douro Superior) in north-eastern Portugal. These DO/sub-regions are projected to become much drier than currently so that irrigation or the introduction of new varieties are likely adaptation measures to maintain the viability and sustainability of regional viticulture in future decades.