More than 50 years have passed since 2001: A Space Odyssey debuted in April 1968. In the film, Dr. Heywood Floyd flies to a large artificial gravity space station orbiting Earth aboard a commercial space plane. He then embarks on a commuter flight to the Moon arriving there 25 h later. Today, in this the 52nd anniversary year of the Apollo 11 lunar landing, the images portrayed in 2001 still remain well beyond our capabilities. This article examines key technologies and systems (e.g., in situ resource utilization, fission power, advanced chemical and nuclear propulsion), and supporting orbital infrastructure (providing a propellant and cargo transfer function), that could be developed by industry for both NASA and future commercial ventures over the next 30 years, allowing the operational capabilities presented in 2001 to be achieved, although on a more Spartan scale. Lunar-derived propellants (LDPs) will be essential to developing a reusable lunar transportation system that can allow initial outposts to evolve into settlements supporting a variety of commercial activities. Deposits of icy regolith discovered at the lunar poles can supply the feedstock material needed to produce liquid oxygen (LO2) and liquid hydrogen (LH2) propellants. On the lunar nearside, near the equator, iron oxide-rich volcanic glass beads from vast pyroclastic deposits, together with mare regolith, can provide the feedstock materials to produce lunar-derived LO2 plus other important solar wind implanted (SWI) volatiles, including H2 and helium-3. Megawatt-class fission power systems will be essential for providing continuous “24/7” power to processing plants, human settlements and commercial enterprises that develop on the Moon and in orbit. Reusable lunar landing vehicles will provide cargo and passenger “orbit-to-surface” access and will also transport LDP to Space Transportation Nodes (STNs) located in lunar polar (LPO) and lunar equatorial orbits (LLO). Reusable space-based, lunar transfer vehicles (LTVs), operating between STNs in low Earth orbit (LEO), LLO, and LPO, and able to refuel with LDPs, offer unique mission capabilities, including short transit time crewed cargo transports. Even commuter flights similar to that portrayed in 2001 appear possible, allowing 1-way trip times to and from the Moon as short as 24 h. The performance of LTVs using both RL10B-2 chemical rockets and a variant of the nuclear thermal rocket (NTR), the LO2-Augmented NTR (LANTR), are examined and compared. If only 1% of the LDP obtained from icy regolith, volcanic glass, and SWI volatile deposits were available for use in lunar orbit, such a supply could support routine commuter flights to the Moon for many thousands of years. This article provides a look ahead at what might be possible in the not too distant future, quantifies the operational characteristics of key in-space and surface technologies and systems, and provides conceptual designs for the various architectural elements discussed.