The mission requirements of crewed space vehicles flown by NASA drove the development of new techniques for burn targeting and guidance for ascent, rendezvous, lunar landing, and deorbit. The Saturn V Iterative Guidance Mode used an approximately optimal steering law that could adjust the trajectory to compensate for performance issues while meeting trajectory constraints at propulsion-system cutoff. Hypersurface targeting provided constraints for the Saturn V Trans-Lunar Injection burn. E Guidance, in quadratic- and linear-acceleration forms, provided closed-loop descent and ascent guidance for the Apollo Lunar Module. The Space Shuttle’s Powered Explicit Guidance algorithm was more flexible than Apollo-era guidance algorithms, and it had better convergence characteristics, enabling it to support challenging abort profiles. The Space Launch System has built on the heritage of the Space Shuttle’s guidance algorithm. The Orion spacecraft’s Two-Level Targeter enables onboard, autonomous targeting of an entire mission profile subject to three-body dynamics in cislunar space. Orion uses Shuttle-derived guidance as the basis for an orbit-guidance package with more capability than guidance algorithms of previous vehicles.