This work focuses on the reliability-based design of isolation systems. In particular, the design of isolation systems for large scale building models under uncertain excitation is considered. Isolation systems composed by rubber bearings are used in the present formulation. The non-linear behavior of these devices is characterized by a biaxial hysteretic model which is calibrated from experimental data. The variability of future excitations is addressed by adopting a probabilistic approach. The design problem of the isolation system is formulated as a nonlinear constrained minimization problem. Reliability is quantified as the probability that the response quantities of interest do not exceed acceptable performance bounds within a particular reference period. Such probabilities are estimated by an advanced simulation technique. An example problem defined in terms of a large finite element building model shows the effectiveness of the proposed design process.