Experimental investigations showed that the microstructure of polycrystalline metallic materials may have a significant influence on the fatigue life at low loading amplitudes. Anisotropic elastic properties of the individual grains as well as manufacturing-induced residual stresses cause local stress concentrations under external load. The investigations revealed that the consideration of the three-dimensional microstructure is essential for a realistic determination of the stress distribution. These stress concentrations cause plastic shear in form of dislocation generation and motion on crystallographic planes exhibiting a high Schmid factor. This dislocation motion is only partially reversible, even under fully reversed loading. The accumulation of the irreversible fraction of this local plastic deformation over many load cycles can cause crack nucleation. Also, the subsequent short crack propagation, which frequently takes place on just one crystallographic plane, is determined by the stress distribution on this length scale. Furthermore, fatigue microstructural short cracks can strongly interact with microstructural barriers, such as grain and phase boundaries. Under certain circumstances, this can cause a permanent stop of crack propagation. Hence, specific microstructural features can give rise to a real fatigue limit despite the presence of initiated fatigue cracks. A model for a three-dimensional simulation of fatigue crack nucleation and microstructure-dominated short fatigue crack propagation is presented, which considers the physical processes on the microstructure level in a mechanism-based manner. The model is verified by means of a comparison between experiments and simulation results. By means of the modelling concept a quantitative assessment of the resistance of real and synthetic microstructures to the initiation and propagation of short fatigue cracks is possible. Hence, the simulation results contribute to the development of tailored microstructures for improved fatigue resistance.