The growth and development of plants during spaceflight have important implications for both basic and applied research supported by NASA and other international space agencies. While there have been many reviews of plant space biology, the present chapter attempts to fill a gap in the literature on the actual process and methods of performing plant research in the spaceflight environment. The author has been a principal investigator on six spaceflight projects and has another two space experiments in development. These experiences include using the US Space Shuttle, the former Russian space station Mir, and the International Space Station, utilizing the Space Shuttle and Space X as launch vehicles. While there are several ways to obtain a spaceflight opportunity, this review focuses on using the NASA peer-reviewed sciences approach to get an experiment manifested for flight. Three narratives for the implementation of plant space biology experiments are considered from rapid turnaround of a few months to a project with new hardware development that lasted 6 years. The many challenges of spaceflight research include logistical and resource constraints such as crew time, power, cold stowage, and data downlinks, among others. Additional issues considered are working at NASA centers, hardware development, safety concerns, and the engineering versus science culture in space agencies. The difficulties of publishing the results from spaceflight research based on such factors as the lack of controls, limited sample size, and the indirect effects of the spaceflight environment also are summarized. Finally, lessons learned from these spaceflight experiences are discussed in the context of improvements for future space-based research projects with plants.