Structures are often subjected to multiaxial cyclic load superimposed with a mean-stress. Thus, both the mean stress effect and the biaxiality effect are needed to be addressed for a proper design. Steels (Cr-Mo) used for such structures often contain manufacturing defects. Mean-stresses were found to control the crack initiation sites: at low mean-stresses, fatigue cracks initiated from the surface, while for high mean-stresses cracks initiated from internal or surface-cutting defects. This transition can be explained by the stress and strain fields around the defects. Moderate stress biaxialities had a beneficial effect on fatigue lives, attributed mainly to a retardation of crack initiation, while equibiaxial tension had a slightly detrimental effect, attributed to a “pseudo size effect”: higher probability for an incipient crack to grow along two possible planes, compared to a single one. An empirical fatigue criteria based on Gerber’s parabola was able to captured the evolution of the endurance limit under the combined effects of a positive mean stress and positive biaxiality.