The development of a general framework for reliability-based design of base-isolated structural systems under uncertain conditions is presented. The uncertainties about the structural parameters as well as the variability of future excitations are characterized in a probabilistic manner. Nonlinear elements composed by hysteretic devices are used for the isolation system. The optimal design problem is formulated as a constrained minimization problem which is solved by a sequential approximate optimization scheme. First excursion probabilities that account for the uncertainties in the system parameters as well as in the excitation are used to characterize the system reliability. The approach explicitly takes into account all non-linear characteristics of the combined structural system (superstructure-isolation system) during the design process. Numerical results highlight the beneficial effects of isolation systems in reducing the superstructure response.