The crack growth resistance of the Al-Zn-Mg-Cu alloy forgings in overaged condition was investigated with three industrially produced alloys, which showed differences in the microstructures governed by compositional variations. Fatigue-crack propagation experiments were conducted at ambient temperature and variations in crack growth rates (da/dN) as a function of applied stress intensity range (ΔK) were related to the characteristics of microstructures, including coarse intermetallic (IM) particles and precipitates. It appears that the crack growth rate increases systematically with an increase of the impurity level, which in turn increases the amount and size of large Fe- and Si-containing IM particles while decreases their spacing. That degradation in resistance to crack growth was attributed to the acceleration of the crack initiation and propagation by coarse IM particles were confirmed by in-situ SEM observation of the fracture process. The observed anisotropy in fatigue behavior was caused by the anisotropy in coarse IM particle orientation.