ABSTRACTThis article examines Loss‐Driven Systems Engineering (LDSE) utility via a thought experiment regarding harmonizing desirable characteristics for resilience, safety, reliability, security, and other loss‐driven specialty areas. Various design reference missions explore and assess required loss‐driven capabilities in automated flight operations for a hypothetical Manned Space Rescue Vehicle. Identifying key adversities to achieving mission success, and evaluating potential methods to avoid, withstand, and recover from loss caused by such adversities are central to this assessment. Such methods apply classical technical disciplines such as resilience, safety, reliability, survivability, and security in an integrated fashion, recognizing and respecting each discipline's expertise and proven methods, tools, and techniques. This article also examines the concurrent need to consider loss‐driven solution unintended consequences: the “First Do No Harm” medical concept ensuring adversity's “cure cannot be worse than the disease.” Finally, this article examines the potential to leverage flexibility and creativity in crew actions and adaptive systems to overcome unexpected adversity.