NASA pursuit of human missions Beyond Earth Orbit (BEO) to the moon and eventually Mars will pose many new challenges. These missions are characterized by increased risks to human performance due to stress, fatigue, radiation exposure, and isolation. Fundamental changes in spaceflight operations will be required as well. A very critical part of future missions will be assisting the crew with problem-solving and contingency resolution using next-generation smart spacecraft systems. Human Systems Integration (HSI) must be included as part of the systems engineering process. Gateway 1 will serve as part of the proving ground for maturing technology such as autonomous systems and space operations procedures to help meet moon mission goals and prepare humans for missions to Mars. For deep space missions, risk factors affecting humans such as mission duration, distance, and physiological/psychological effects, must be considered. A human is not a simple component but rather a system in a systems-of-systems application-a system influenced by cognitive and biological factors that are difficult to model/analyze. System complexity will demand an integrated approach that requires multiple viewpoints, including the understanding of the astronauts' capabilities and limitations to enhance safety, performance, and satisfaction on the interaction between all system users in a variety of environments to achieve acceptable mission goals and performance. HSI will play a vital role in the development of these future missions. This paper provides a discussion of HSI used at NASA and the critical role human factors engineering will play in the HSI process for future missions along with the challenges. Industries such as oil and gas (O&G) could benefit from the content of this paper to help improve the safety and operations of deepwater/oil and gas exploration activities. NASA engineering and human systems subject-matter expert personnel reviewed challenges reported in space-related environments for long space duration missions and identified similarities with the challenges encountered in deepwater exploration. The researchers noted the space industry's current solutions and proposed a system development view to solve future deepwater exploration challenges using HSI principles. This paper discusses the results of the review.