Since the usability of castings is influenced by the presence of immanent defects, the aim of this work is to investigate the effects of cast steel imperfections on the long life fatigue strength and to enable the assessment based on generalized fracture mechanics. For this purpose, the cast steel material G21Mn5 in normalized condition is utilized for the characterization of the fundamental fatigue, fracture mechanical as well as quasi-static parameters. Initially, the near-defect-free material strength is investigated by means of plain specimens, whereby different load stress ratios are examined. Furthermore, specimens exhibiting circumferential V-shaped notches with varying opening angles are investigated, which confirms a fundamental applicability of the generalized fracture mechanics. For this purpose, the notched specimen geometries are evaluated numerically according to the concept of the notch stress intensity factors. Subsequent numerical casting simulations support the development of defect-afflicted large-scale specimens, which serve the transferability from notched specimens towards shrinkage imperfections of the presented concept. Based on the results of the imperfective specimen’s fractographic analysis and of the fracture mechanical investigations, numerical crack propagation simulations are carried out, which subsequently enables the geometrical substitution of an actual casting flaw by a fracture mechanical-equivalent penny-shaped geometry. Finally, a defect evaluation based on the generalized Kitagawa diagram as well as a comprehensive elastic and elasto-plastic strain-energy-density-based assessment methodology is facilitated, taking into account the evaluated material parameters and the results of the numerical simulations. The introduced approaches for the evaluation of imperfective large-scale cast steel specimens exhibits a sound agreement with the experimentally determined data, whereby defect-related data are taken either from the fracture surfaces or from conducted X-ray scans. In contrast to the methods currently used in the evaluation of imperfective components, which are mostly based on a qualitative comparison with reference X-ray radiographs, these extended fracture mechanical and strain energy density approaches allow an absolute evaluation of the fatigue strength impaired by inherent defects, whereat the local defect geometry is taken uniformly into account and thus facilitates a mutual link between defects, such as shrinkage pores, and crack-like imperfections by generalized fracture mechanics.