Probabilistic microstructurally-based models for fatigue are being developed as part of a DARPA/Northrop Grumman Structural Integrity Prognosis System (SIPS). An integrated framework has been developed to provide probabilistic fatigue life prognosis of individual air vehicles by leveraging research across a large multidisciplinary team. Development of the framework was made possible by advancements made by the SIPS Modeling and Simulation multidisciplinary research team in the statistical modeling of polycrystalline metal microstructures, finite element meshing, multiscale analysis, modeling of constitutive behavior of polycrystals, and materials testing technology for property measurement and validation procedures. The fatigue models are based on a fundamental understanding of the fatigue process, and trace the structural degradation caused by fatigue back to its physical origins in the microstructure of the metallic component. The objectives are to discover and link all the important damage mechanisms leading to a macroscopically observable crack and to allow defects to emerge naturally from statistically meaningful ensembles of material representations, subject to more accurate, scale-specific, damage inducing fields. An example is modeling the interplay between the grain crystallography and crack incubation at a constituent particle. A microstructurally-based model allows estimation of the total fatigue life from incubation and nucleation at a constituent second phase particle to propagation of micro-cracks to emergence of macro-cracks all in a statistical sense to permit accurate estimation of reliability indices. Dedication This paper is dedicated in memory of Dr. John M. Papazian, principal investigator on the SIPS program, our technical leader and friend, who worked tirelessly to bring his vision of the program to fruition. John's wisdom, leadership and love of life have been a true inspiration.