Among the many historical buildings in Italy, the Ducal Palace in Urbino (15th century) was chosen in order to study the weathering of stones at a relatively unpolluted site. The main mechanisms of the physical and chemical processes leading to natural weathering could therefore be identified without interference from high pollution levels, such as found in cities, where sulfation dominates. A microclimatic study was carried out in order to determine both the seasonal and diurnal thermal and hygrometric cycles and exchanges of heat and vapor between the stone and the atmosphere. A comparison of environmental forcing cycles over deteriorated zones, led to the conclusion that processes induced by microclimate play a negligible role compared with those induced by liquid water supplied by rainfall. The chemical and physical processes of stone weathering, due both to the dissolution and recrystallization of calcium carbonate, and to transformation and crystallization of gypsum inside the stone, were identified. A process of stone weakening due to the internal circulation of rain water is demonstrated. Finally, some suggestions have been made for a more effective conservation of the artistic heritage.