Skeletal muscle satellite cells play an essential role in muscle regeneration and exercise adaptation. In recent years atypical myogenic progenitors (non–satellite‐cell muscle stem cells) have been identified in skeletal muscle and have been hypothesized to play an important role in the process of muscle regeneration. It remains unknown, however, whether any populations other than satellite cells play a significant role in repair and adaptation following exercise‐induced damage. We assessed the response of the satellite cell population and the CD45⁺:Sca‐1⁺ cell population, previously shown to support muscle regeneration following cardiotoxin‐induced injury, after acute eccentrically biased exercise in wild‐type mice. We observed evidence of focal muscle damage and repair following the exercise protocol using electron microscopy, hematoxylin–eosin staining, and single‐fiber analysis. In addition, we observed an approximately sixfold increase in the number of Myf5‐expressing cells by 48 h, which remained elevated until at least 96 h following exercise. We did not, however, observe any significant expansion of the CD45⁺:Sca‐1⁺ cell population or commitment of resident CD45⁺:Sca‐1⁺ cells to the myogenic lineage. Furthermore, expression of Wnt gene family members, previously associated with myogenic specification of CD45⁺:Sca‐1⁺ cells, did not differ following exercise. Therefore, we conclude that muscle satellite cells are the primary responders to exercise‐induced stress and that the CD45⁺:Sca‐1⁺ myogenic progenitors do not contribute to muscle repair/adaptation following exercise. Muscle Nerve, 2008