ABSTRACT Common acute injuries to skeletal muscle can lead to significant pain and disability. The current therapeutic approaches for treating muscle injuries are dependent on the clinical severity but not on the type of injury. In these studies, the pathophysiology and molecular pathways associated with two different types of skeletal muscle injury, one induced by direct destruction of muscle tissue (i.e., FI) and one induced by a contractile overload, more specifically high-force eccentric contractions (i.e., CI) were compared side by side. Histopathological evaluation and measurements of muscle strength were accompanied by analyses of expression for 12,488 known genes at four time points ranging from 6 hours to 7 days post-injury. Real-time RT-PCR was used to confirm some of the injury type differences in the gene expression temporal profiles. Our data revealed several pools of genes including early induction of transcription, myogenic, and stress-responsive factors common for both types of injury as well as pools of genes expressed specifically with one of the injury type. Only CI activated a set of genes associated with the repair of impaired proteins and structures including genes related to apoptosis, whereas while FI uniquely activated gene sets involved gene sets involved in extensive inflammatory responses, tissue remodeling, angiogenesis, and myofibre/extracellular matrix synthesis. In conclusion, sets of genes associated specifically with the nature of the injury may have application for development of new strategies for acceleration of the recovery process in injured skeletal muscle.