Rhabdomyolysis is a syndrome characterized by muscle necrosis and the release of intracellular muscle constituents into the circulation. Consequently, the circulatory levels of intracellular molecular components, such as creatine kinase, are commonly used to evaluate the severity of muscle damage. Nevertheless, there is a wide inter-individual variability in the phenotypic expression of muscle damage, which cannot be predicted by the age, race, body composition, and fitness level of each subject. This suggests that apart from environmental factors, genetic factors might also contribute to the development and progression of exercise-induced muscle damage. Recently, several gene-specific single nucleotide polymorphisms (SNPs) were found to be associated with severe exercise-induced muscle damage. The present manuscript reviews the pathophysiology of exertional muscle damage, emphasizing the influence of gene polymorphisms on its inter-individual severity. This knowledge may be useful for pediatricians for identifying individuals more susceptible to severe exertional muscle damage and related life-threatening comorbidities.