Critical rotating components used in the hot section of gas turbine engines are subject to cyclic loading conditions during operation, and the life of these structures is governed by their ability to resist fatigue. Since it is well known that microstructural parameters, such as grain size, can significantly influence the fatigue behavior of the material, the conventional processes involved with the manufacture of these structures are carefully controlled in an effort to engineer the resulting microstructure. For a commercial Ni-base superalloy, RR1000, the development of process models and deformation mechanism maps has enabled not only control of the resultant grain size but also the ability to tailor and manipulate the resulting grain boundary character distribution. The increased level of microstructural control was coupled with a physics-based fatigue model to form an integrated computational materials engineering framework that was used to guide the design of damage-tolerant microstructures. Simulations from a 3D crystal plasticity finite element model were used to identify microstructural features associated with strain localization during cyclic loading and to guide the design of polycrystalline microstructures optimized for fatigue resistance. Conventionally processed and grain boundary engineered forgings of a commercial Ni-based superalloy, RR1000, were produced to validate the design methodology. For nominally equivalent grain sizes, high-resolution strain maps generated via digital image correlation confirmed that the high density of twin boundaries in the grain boundary engineered material were desirable microstructural features as they contribute to limiting the overall length of persistent slip bands that often serve as precursors for the nucleation of fatigue cracks.