The alloy design and homogenization processes are intimately associated with the microstructure, phase composition and performance for Al-Zn-Mg-Cu alloys. The microstructures and phase composition of a series of Al-Zn-Mg-Cu alloys before and after the homogenization treatments were investigated along with thermodynamic calculation to understand the underlying relationship. The eutectic microstructures (α-Al + M (Mg(ZnAlCu)2)) are dominating with Cu-enriched [AlCuMgZn] particles, both depending on the Zn:Mg ratio and (Cu + Mg) content, in addition to minor constituent θ (Al2Cu) and Al7Cu2Fe phases in the as-cast alloys. The optimal homogenization process was suggested based on the analysis of the residual phases (i.e., the S (Al2CuMg) phase) since all (for low/mediate-(Cu + Mg) alloys) or partially (for high-(Cu + Mg) alloys (∼>4.24 wt%)) S (Al2CuMg) particles were dissolved during the homogenization. This residual S phase may be transformed from the primary M and/or Cu-enriched [AlCuMgZn] phases. The homogenization kinetics calculation results agreed well with above experimental results. A critical (Cu + Mg) level and a linear correlation between Cu and Mg concentrations were revealed based on the thermodynamically modelling, which can be conductive to determine the optimal homogenization process. Furthermore, the solubility limit and stoichiometric balance principles based on controlling the homogenized microstructures can guide the composition design for advanced high-strength aluminum alloys.