To meet operational efficiency and productivity demands of the 21st century marketplace, aerospace and transportation sector platforms are being driven to incorporate increasingly larger and more highly stressed unitized structural components. This recent trend has prompted the need for improved fatigue crack growth characterization methodologies to understand impact of relevant mixed-mode loading conditions on crack growth direction and life estimation. This paper describes the development of an Alcoa capability to study and model fatigue crack growth behavior under combined mode I and mode II loading in high-strength aluminum products. The objective is to demonstrate the experimental capability necessary to improve the basic understanding of the roles and synergistic effects of mixed-mode loading (modes I and II) and microstructural resistance, as they relate to fatigue crack growth direction and life estimation. The particular alloy selected for this study is aluminum alloy (AA) 7050-T7651 thick plate taken to be representative of a widely used material for aircraft thick structural parts. The specimens chosen for this capability study are based on the compact tension shear (CTS) specimen documented in the literature. Results are presented to demonstrate the development of stress-intensity factor and compliance solutions to automate the fatigue precracking step. Full-field strain measurements for a notched specimen are used to further validate the finite element analysis. In addition, preliminary results are presented to explore the feasibility of a Keq approach based on total strain-energy release rate to evaluate similitude in the fatigue crack growth rate relationship for the mixed-mode loading case. Preliminary fatigue crack growth test results show that under combined modes I and II loading, the fatigue crack growth rate and direction depend strongly on the competition between the mixed-mode crack-tip driving force and microstructural planes offering the weakest crack growth resistance.