High frequency push-pull fatigue experiments on the austenitic-ferritic duplex stainless steel X2CrNiMoN22-5-3 (318LN) revealed that crack nucleation and crack propagation through the first grain determine significantly the lifetime of the material. Only in very few cases it was observed that fatigue samples which endured one billion load cycles without failure (run-out samples) contain microcracks which reached or overcame the first microstructural barrier (phase or grain boundary). This leads to the conclusion that in most cases the highest macroscopic stress or strain amplitude which does not lead to fatigue crack propagation through the entire first grain can be considered as the fatigue limit of the material. The present study documents that the experimentally identified fatigue mechanisms can be represented in mesoscopic finite element simulations by taking into account the effects of anisotropic elasticity, crystal plasticity, macro and micro residual stresses, plastic strain concentration in form of slip bands, crack nucleation and short crack propagation through the first grain. The current investigation shows that such simulations enable the determination of the fatigue limit of both real and synthetic microstructures. By means of real microstructures, containing slip traces and microcracks, the calculations can be verified and the required microstructural parameters can be determined.