The scientific study of teamwork in the context of spaceflight has uncovered a considerable amount of knowledge over the past 20 years. Although much is known about the underlying factors and processes of teamwork, much is left to be discovered for teams who will be operating in extreme isolation and confinement during a future Mars mission. Special considerations must be made to enhance teamwork and team well-being for multi-year missions during which the small team will live and work together. We discuss the unique challenges of effective teamwork in a Mars mission scenario, and the difficulties of studying teamwork using analogs of the space environment. We then describe the National Aeronautics and Space Administration’s current practices and research on teamwork, which includes team selection and composition, teamwork training, countermeasures to mitigate risks to effective team performance, and the measurement and monitoring of team functioning. We end with a discussion of the teamwork research areas that are most critical for a successful journey to Mars.