Structural safety under fire has received significant attention in recent years. Current approaches to structural fire design are based on prescriptive codes that emphasize insulation of steel members to achieve adequate fire resistance. The prescriptive approach fails to give a measure of the true performance of structural systems in fire and gives no indication of the level of reliability provided by the structure in the face of uncertainty. The performance-based design methodology overcomes many of the limitations of the prescriptive approach. The quantification of the structural reliability is a key component of performance-based design as it provides an objective manner of comparing alternative design solutions. In this study, a probabilistic framework is established to evaluate the structural reliability under fire considering uncertainties that exist in the system. The structural performance subjected to realistic fires is estimated by numerical simulations of sequentially coupled fire, thermal, and structural analyses. In this dissertation, multiple reliability methods (i.e., Latin hypercube simulation, subset simulation, and the first/second order reliability methods) are extended to investigate the structural safety under fire.The reliability analysis of structures in fire involves (i) the identification and characterization of uncertain parameters in the system, (ii) a probabilistic analysis of the thermo-mechanical response of the structure, and (iii) the evaluation of structural reliability based on a suitable limit state function. Several applications are considered involving the response of steel and steel-concrete composite structures subjected to natural fires. Parameters in the fire, thermal, and structural models are characterized, and an improved fire hazard model is proposed that accounts for fire spread to adjacent rooms. The importance of various parameters is determined by considering the response sensitivity, which is determined by finite difference and direct differentiation methods. The accuracy and efficiency of the various reliability methods, as applied to structures in fire, are compared, and the strengths and weaknesses of each approach are identified.