A model is constructed for prediction of fatigue crack initiation based on the material’s microstructure. Our approach is to model the energy of a persistent slip band (PSB) structure and use its stability with respect to dislocation motion as our failure criterion for fatigue crack initiation. The components that contribute to the energy of the PSB are identified, namely, the stress field resulting from the applied external forces, dislocation pile-ups, and work-hardening of the material is calculated at the continuum scale. Further, energies for dislocations creating slip in the matrix/precipitates, interacting with the GBs, and nucleating/agglomerating within the PSB are computed via atomistics. The predicted fatigue life is driven by the microstructure such as grain orientations, widely distributed grain sizes, precipitates, PSB-GB interactions, as well as the effect of neighboring grains. Excellent agreement is shown between the model predictions and experimental data.