During approach to a remote island location, a U.S. Air Force heavy-airlift aircraft was flown into an aerodynamic stall, resulting in the loss of more than 4000 ft of altitude, with the crew recovering the aircraft just before impact would have occurred. An analysis of the mishap was conducted through a review of non-privileged USAF mishap data, cockpit voice recordings, flight data records, and interviews of the aircrew involved. A thorough examination of fatigue-related factors was conducted, including computerized fatigue modeling. The crew traveled over 11,000 mi in a westward direction over a 6-d period. They had been on duty for nearly 21 h on the day of the mishap, with minimal in-flight rest. The pilots were late beginning their descent for landing, and a minor aircraft malfunction distracted the crew, contributing to channelized attention and degraded situational awareness. A breakdown in crew communication and failure to adequately monitor and interpret true aircraft state culminated in loss of aircraft control. Analysis of the crew's work/rest schedule confirmed that multiple elements of fatigue were present during this mishap, including acute and cumulative fatigue, circadian disruptions, and sleep inertia. Additionally, reduced situational awareness and spatial disorientation, exacerbated by the underlying fatigue, were causal in this mishap. This mishap highlights the importance of maintaining a high degree of situational awareness during long-haul flights with a continuing need to address issues regarding spatial disorientation, proper application of human engineering principles in modern cockpits, and mitigation of aircrew fatigue factors.