Tunnels are constructed increasingly close to existing buried structures, including pile foundations. This poses a serious concern, especially for tunnels built beneath piles. Current understanding of the global tunnel-soil-pile-building interaction effects is lacking, which leads to designs which may be overly conservative or the adoption of expensive measures to protect buildings. This paper presents outcomes from 24 geotechnical centrifuge tests that aim to investigate the salient mechanisms that govern piled building response to tunnelling. Centrifuge test data include greenfield tunnelling, pile loading, and tunnelling beneath single piles and piled frames, all within sand. The global tunnel-piled frame interaction scenario is investigated using a newly developed real-time hybrid testing technique, wherein a numerical model is used to simulate a building frame, a physical (centrifuge) model is used to replicate the tunnel-soil-foundation system and structural loads, and coupling of data between the numerical and physical models is achieved using a real-time load-control interface. The technique enables, for the first time, a realistic redistribution of pile loads (based on the superstructure characteristics) to be modelled in the centrifuge. The unique dataset is used to quantify the effects of several factors which have not previously been well defined, including the pile installation method, initial pile safety factor, and superstructure characteristics. In particular, results illustrate that pile settlement and failure mechanisms are highly dependent on the pre-tunnelling loads and the load redistribution that occurs between piles during tunnel volume loss, which are related to structure weight and stiffness. The paper also provides insight as to how pile capacity should be dealt with in a tunnel-pile interaction context.