Launching a NASA radioisotope power system (RPS) mission requires compliance with two Federal mandates: the National Environmental Policy Act of 1969 (NEPA) and launch approval (LA), as directed by Presidential Directive/National Security Council Memorandum 25. Nuclear safety launch approval lessons learned from multiple NASA RPS missions, one Russian RPS mission, two non-RPS launch accidents, and several solid propellant fire test campaigns since 1996 are shown to have contributed to an ever-growing body of knowledge. The launch accidents can be viewed as “unplanned experiments” that provided real-world data. Lessons learned from the nuclear safety launch approval effort of each mission or launch accident, and how they were applied to improve the NEPA/LA processes and nuclear safety of subsequent RPS missions, are presented. The current emphasis on cost improvements to future NEPA/LA processes are placed into context of these historical nuclear safety improvements, with a caution that certain cost improvements may have the short-term effect of lowering NEPA/LA costs but at the expense of curtailing potential nuclear safety improvements. The reader should note that changes are not made lightly, and a benefit is sought through the change. These improvements may be in other areas besides cost.