In-space propellant re-supply has been proposed to extend space vehicle lifetimes, but only qualitative arguments supporting development have been made; this study focuses on quantitative support. Two basic concepts for propellant re-supply are propellant transfer and tank replacement. A quantitative assessment and comparison to no re-supply alternatives is necessary to choose the most cost-effective architecture. The analysis is primarily accomplished through the use of a new tool that facilitates propulsion system sizing and broad trade studies. The program was co-created by the author under a grant from NASA Langley Research Center and has been used at NASA Langley for lunar architecture studies to support the Vision for Space Exploration. For less than 100 missions, the preferred scenario is without re-supply, using direct Earth reentry. For more than 100 missions, tank replacement requires 38% fewer missions than propellant transfer to become more cost effective than no re-supply.