BACKGROUND Numerous authors have identified the stressors likely to be encountered on long duration space exploration missions (e.g., to Mars), including the possibility of significant crises, separation from family, boredom/monotony, and interpersonal conflict. Although many authors have noted that meaningful work may be beneficial for astronauts on these missions, none have detailed the sources of meaningful work for astronauts and how these sources may differ between astronauts. The present article identifies how engagement in meaningful work during long duration missions may mitigate the adverse effects of demands and increase the potential for benefits resulting from the missions. METHODS Semistructured interviews were conducted with nine NASA personnel, including astronauts, flight directors, and flight surgeons. Questions addressed sources of meaning for astronauts, characteristics of tasks that enhance vs. detract from meaning, and recommendations for enhancing meaning. RESULTS Personnel mentioned contributing to humanity and the next generation, contributing to the mission, and exploration as the most meaningful aspects of their work. Characteristics of tasks that enhanced meaning included using a variety of skills, feeling personal control over their schedule, autonomy in the execution of tasks, and understanding the importance of the experiments conducted on the mission. Top recommendations to sustain meaning were insuring social needs were met through such activities as the strategic use of social media, giving astronauts autonomy as well as structure, and conducting training during transit. CONCLUSIONS Implications are addressed for tailoring meaning-based interventions for astronauts participating on long duration missions and assessing the effectiveness of these interventions.Britt TW, Sytine A, Brady A, Wilkes R, Pittman R, Jennings K, Goguen K. Enhancing the meaningfulness of work for astronauts on long duration space exploration missions. Aerosp Med Hum Perform. 2017; 88(8):779-783.