AbstractDimensioning with high‐strength steels relies on the knowledge of Wöhler‐type S/N data and the assumption that no failure occurs for load levels below the fatigue limit for applications where the number of load cycles exceeds 107. Very‐high‐cycle fatigue (VHCF) experiments applied to a 0.5C‐1.0Cr‐Mo tempered steel (German designation: 50CrMo4) revealed surface crack initiation at prior austenite grain boundaries in medium strength condition (37HRC) and internal crack initiation at nonmetallic inclusions at high strength condition (57HRC). Despite the formation of small cracks during cycling up to 109 cycles, it seems that these are nonpropagating cracks in the case of the medium strength condition and therefore a real fatigue limit exists. Application of automated electron back‐scatter diffraction (EBSD) within the shallow‐notched area of electro‐polished fatigue specimens had shown that prior austenite grain boundaries act as effective obstacles to crack propagation. High‐resolution thermography during cycling of the specimens allowed the identification of local plasticity, which led to crack initiation at a later stage of the fatigue life. It was found that Cr segregation rows play a decisive role in the crack initiation process. By means of high‐resolution electron microscopy in combination with focused ion beam milling (FIB), evolution of cyclic plasticity and crack initiation was correlated with the material's microstructure. The results are discussed in terms of the completely different crack initiation mechanisms of medium and high strength variants of the same steel. EBSD microstructure and crack propagation data are used to adapt a numerical modeling tool to predict microcrack propagation in the VHCF regime.