The present study documents how the irreversible fraction of cyclic plastic strain, induced by loading amplitudes close to the durability limit, causes fatigue damage such as (i) slip band development, (ii) fatigue crack initiation and (iii) short fatigue crack propagation. The damage evolution of the austenitic–ferritic duplex stainless steel X2CrNiMoN22-5-3 (318 LN) was investigated up to one billion load cycles by means of high resolution electron microscopy (HR-SEM, TEM), focused ion beam (FIB) cutting, confocal laser scanning microscopy (CLSM), in-situ far field microscopy and high-energy (87.1keV) X-ray diffraction (XRD) experiments. The experimentally identified damage mechanisms were implemented into three-dimensional finite element simulations, which consider crystal plasticity. These simulations enable fatigue life predictions of real microstructures obtained for instance by means of, e.g. automated electron back scatter diffraction (EBSD) analysis. The simulations allow for determining whether microcracks (i) initiate in a microstructure, (ii) arrest in the midst of the first grain, (iii) are permanently, (iv) temporary or (v) not at all blocked by grain or phase boundaries. Moreover, this concept is capable to contribute to the concept of tailored microstructures for improved cyclic-loading behavior.