F-22A Raptor is the single-seat, twin-engine, fifth generation stealth fighter aircraft for the United States Air Force. Since 2008, there were over two dozen suspected in-flight hypoxia-like incidence among Raptor pilots. One pilot died on Oct, 2010 after his plane crashed with hypoxia suspected as contributory to the accident. The author tried to solve the puzzle by reviewing openly accessible information including media reports, official accident investigation reports, congressional hearing transcripts, military news transcripts. The possible contributing factors to these mysterious events were analyzed. United State Air Force's remedies to some of the faulty designs were disclosed. Several important issues derived from this study are worthy of learning and discussion among fellow aerospace medicine and aerospace physiology practitioners.