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Seismic resiliency includes the ability to protect the contents of mission-critical buildings from becoming damaged. The contents include telecommunication and other types of electronic equipment in mission-critical data centres. One technique to protect sensitive equipment in buildings is the use of floor isolation systems (FIS). Multi-directional shake table real-time hybrid simulation (RTHS) is utilized in this paper to validate the performance of full-scale rolling pendulum (RP) bearings, incorporating multi-scale (building– FIS–equipment) interactions. The analytical substructure for the RTHS included 3D nonlinear models of the building and isolated equipment, while the experimental substructure was comprised of the FIS. The RTHS test setup consisted of the FIS positioned on a shake table, where it is coupled to the analytical substructure and subjected to multi-directional deformations caused by the building’s floor accelerations and equipment motion from an earthquake. Parametric studies were performed to assess the influence of different building lateral load systems on the performance of the FISs. The lateral load resisting systems included buildings with steel moment resisting frame (SMRF) systems and with buckling restrained braced frame (BRBF) systems. Each building type was subjected to multi-directional ground motions of different sources and hazard levels. Details of the experimental test setup, RTHS test protocol and main preliminary results on the multi-directional testing of an RP-based FIS are described. Challenges in conducting the multi-axial RTHS, including the nonlinear kinematics transformation, adaptive compensation for the actuator-table dynamics, along with the approaches used to overcome them are presented. The acceleration and deformation response of the isolated equipment is assessed to demonstrate the effectiveness of the FIS in mitigating the effects of multi-directional seismic loading on isolated equipment in mission-critical buildings.