Most often efforts to protect the cultural heritage buildings are focused on a specific structure. Available sources are spent for protecting the very structure from certain hazards or deterioration while the “big picture”, which is the holistic risk of the cultural heritage site, is omitted. This paper presents a scientific project funded to help in mitigating seismic risks in historical peninsula of Istanbul where Eastern Rome, Byzantine and Ottoman structures populate almost every street. The region in question is in UNWorld Heritage List but is also in extremely close proximity, in the order of 10 to 13 km, to a major fault that generates large-magnitude earthquakes in every one-and-a- half century in average. The main activities of the project consist of creating a strong ground motion and ambient vibration network, building and testing large-scale specimens to define limit states of the masonry heritage structures and combining the monitoring and testing findings with computer modelling tools.