For many years, the Silk Road acted as a powerful vehicle for cultural and religious diffusion, in parallel with the trade that underpinned its very existence. The purpose of this article is to analyse Portugal’s role in the construction of the sea routes and the way Macao fits into this context. The starting point is the history of the Silk Road, which shows that the various networks built up over time by monks, priests, soldiers, nomads and pilgrims, with their emphasis on religion and trade, also served as channels for the inter-civilizational dissemination of culture and knowledge. From the 15th century onwards, sea routes became an integral part of the existing networks. This was particularly the case for the routes developed by Portugal and Spain, who led the very first wave of globalisation. The later emergence of the great global empires of the 19th and 20th centuries had a significant impact on the Portuguese empire and Macao. China’s new Silk Road project seeks to revive cooperation between various cities, in different countries, that were part of the original Silk Road and that, in the future, can share the benefits of this heritage, through new interconnections and new sustainable routes.