Advanced high strength steels (AHSS) offer a good balance of strength, durability, crash energy absorption and formability. Applications of AHSS for lightweight designs of automotive structures are accelerating in recent years to meet the tough new CAFE standard for vehicle fuel economy by 2025. At the same time, the new generation pickup cargo box is to be designed for a dramatic increase in payload. Upgrading the box material from conventional mild steels to AHSS is necessary to meet the conflicting requirements of vehicle light weighting and higher payload. In this paper, typical AHSS grades such as DP590 and DP780 were applied to selected components of the pickup cargo box for weight reduction while meeting the design targets for fatigue, strength and local stiffness. An automatic gauge optimization process was developed using HyperStudy®, in conjunction with NX™ Nastran for stress analysis and FE-Safe® for multi-axial duty-cycle parent metal fatigue analysis under a measured full durability schedule of proving ground loads. A fatigue life design target (or the calculated fatigue lives at critical locations in the baseline design if they did not meet the target) was applied as the optimization constraints. A total of 7% weight reduction was achieved with the application of AHSS without deteriorating the fatigue, strength and stiffness performance of the cargo box.