In Situ Resource Utilization (ISRU), the use of materials available on-site to replenish supplies or manufacture components, is vital to sustaining human presence in space. In recent years, the abundance of water in the Solar System has been made increasingly clear. Extraterrestrial water, liquid water especially, is of great scientific interest, as targets where water is available are often desirable for future exploration. ISRU with water is therefore a particularly high priority. Water is a vital and versatile resource. It is useable as a working fluid, for propulsion, oxygen production, radiation shielding, irrigation, human consumption, and more. This research explores and develops the systems architecture implications of water as a central spacecraft resource for applications ranging from cislunar nanosatellites to human missions to Mars. Water-electrolysis propulsion provides simple, dense storage of inert propellant to create a safe and reliable means of delivering high ΔV within standard CubeSat specifications. Separation of liquid propellant and electrolyzed gases in microgravity can be achieved with a spinning spacecraft design, saving considerable mass in tankage and valves. Such spacecraft take advantage of damping provided by sloshing liquid water in the propellant tank to provide passive spin stabilization for attitude control purposes. Simulations of the spinning architecture are compared with spinning air bearing tests performed on a mass mockup of water-propelled CubeSats, showing that such stabilization is both feasible and advantageous. The use of water for multiple purposes on those CubeSats, the Cislunar Explorers lunar mission, is presented as a case study in resource-based systems architecture. Water onboard the Cislunar Explorers is used in multiple subsystems: as propellant, for slosh-damping, as a heat sink, and as a radiation shield. The Cislunar Explorers spacecraft do not collect water in-situ but, instead, serve as a pathfinder for demonstrating the utility and versatility of water for future ISRU. If a spacecraft can be propelled with water from Earth, it can be propelled with water from anywhere. The prevalence of water in the Solar System means in-situ resource utilization capability decouples spacecraft from reliance on Earth resources for extended missions. Future mission concepts are explored, including asteroid sample returns and, more extensively, a human mission to Mars utilizing water sourced from cislunar space in propellant depots. Compared to NASA’s Mars Design Reference Architecture, the concept presented achieves a more flexible launch cadence, eliminates the handling and extended storage of cryogenic fluids, and reduces the number of super-heavy lift launch vehicles required for the mission from five to two. The architectures presented benefit from the possibility of public-private partnerships to develop cislunar infrastructure supporting sustained missions beyond Earth orbit with in-situ resource utilization and exploitation. The conclusion considers these possibilities. The result is synergy between the commercial space sector, planned cislunar developments such as the Lunar Orbiting Platform Gateway, and Mars human exploration architectures.