INTRODUCTION: Long-duration spaceflight results in musculoskeletal, cardiorespiratory, and sensorimotor deconditioning. Historically, exercise has been used as a countermeasure to mitigate these deleterious effects that occur as a consequence of microgravity exposures. The International Space Station (ISS) exercise community describes their approaches, biomedical surveillance, and lessons learned in the development of exercise countermeasure modalities and prescriptions for maintaining health and performance among station crews. This report is focused on the first 10 yr of ISS defined as Expeditions 1–25 and includes only crewmembers with missions > 30 d on ISS for all 5 partner agencies (United States, Russia, Europe, Japan, and Canada). All 72 cosmonauts and astronauts participated in the ISS exercise countermeasures program. This Supplement presents a series of papers that provide an overview of the first decade of ISS exercise from a multidisciplinary, multinational perspective to evaluate the initial countermeasure program and record its operational limitations and challenges. In addition, we provide results from standardized medical evaluations before, during, and after each mission. Information presented in this context is intended to describe baseline conditions of the ISS exercise program. This paper offers an introduction to the subsequent series of manuscripts.Hayes J. The first decade of ISS exercise: lessons learned on Expeditions 1–25. Aerosp Med Hum Perform. 2015; 86(12, Suppl.):A1–A6.