We assessed the integrated safety, health, and performance risk to crews on long-duration missions, specifically to Mars. Using a systems approach rather than one focused on individual countermeasures, we examined the trade space around several such risks to identify high-potential risk mitigation strategies and characterize aspects of Mars mission architectures that could lower aggregated risk. Current Mars Design Reference missions would require durations well over two years and would increase crew exposure to radiation and microgravity well beyond ISS levels, likely resulting in significantly reduced performance beyond our current capability to mitigate that could jeopardize mission success. A “fast Mars transit” round-trip mission concept was studied using an innovative flight dynamics approach to quantify the minimum total mission energy required for a Mars transit with total mission duration less than 400 days. This approach holds promise for sending humans to Mars and returning them safely with acceptable, potentially mitigatable, exposure to microgravity and radiation using current or near-term technologies. The fast transit concept would also result in fewer time-driven vehicle failures and enable sustainable deployment of humans and infrastructure to Mars on a regular cadence, allowing steady exploration and colonization of Mars. Finally, we conclude that reliance on the Low Earth Orbit (LEO) mission operations paradigm – i.e., one of near-complete real-time dependence on experts at Mission Control to manage the combined state of the mission, vehicle, and crew – is high risk given the communication delays and limited resupply of any Mars mission, and this risk is not eliminated by the shorter missions durations of fast transit scenarios. Based on historical trends, it is highly likely that the crew will face a high-consequence problem of uncertain origin during Mars transit when ground support will be greatly reduced. While it may be possible to reduce anomaly rates through improved reliability analysis and testing, and to reduce anomaly impacts through added robustness, such mitigations address only known failure modes and known uncertainties. Therefore, a radical shift in the Human-Systems Integration Architecture (HSIA) that defines the operational paradigm, systems design, and human-systems interactions is required to improve the risk posture to an acceptable level regardless of mission duration.