High quality aggregate materials are becoming increasingly scarce and expensive, and therefore optimizing the use of locally available materials is becoming an economic necessity. The research study highlighted in this paper aimed at optimizing the use of varying qualities of aggregate base/granular subbase materials found in Minnesota for achieving cost-effective conventional flexible pavement designs with satisfactory fatigue performances. The methodology consisted of establishing a comprehensive pavement structure sensitivity analysis matrix to include different pavement layer thicknesses and mechanistic material input properties for quality effects and then employing a validated nonlinear finite element program to compute asphalt tensile strains for the various sensitivity matrix variables. The contributions of the unbound aggregate base and granular subbase layers to pavement support and performance were evaluated from a mechanistic-empirical pavement design perspective by incorporating in the analyses cross-anisotropic stress-dependent layer modulus characterizations linked to two different aggregate quality levels (high and low). Aggregate base quality was found to significantly influence bottom-up fatigue cracking; whereas subbase material quality was somewhat important but not as influential as base material quality. Both initial base and subbase construction costs and rutting potential evaluation indicated that the use of marginal quality materials in either base/subbase courses could be cost-effective, depending on the actual pavement thickness and subgrade support conditions.