Sarcopenia and frailty in aging, or cancer cachexia shows an abnormal decrease in skeletal muscle mass and muscle strength. However, the underlying mechanisms are not clear, and the promising drug seeds have not been discovered. The formation of skeletal muscle occurs not only during embryonic development but also in adulthood, and the muscle can be regenerated even if it is damaged by exercise overload or physical injury. Although p38MAPK is ubiquitous among tissues and transmits signal of inflammation and environmental stress into the nucleus, it has been revealed that this kinase is deeply involved in maintaining skeletal muscle homeostasis. Knowledge of p38MAPK accumulated so far suggests that it not only functions as an on-off switch for gene expression, but also it balances cell proliferation and differentiation of progenitor cells to properly respond to muscle damage and repair muscle according to its surrounding environmental cues. In addition, its role in cell fusion to induce myotube formation has been recently revealed. On the other hand, it has been pointed out that in aging and chronic inflammation, excessive enhancement of the p38MAPK activity may disrupt skeletal muscle homeostasis and lead to muscle pathology. Interestingly, animal models have shown that pharmacological manipulation of p38MAPK activity can re-activate aged muscle satellite cells, suggesting the possibility of plastically manipulating skeletal muscle aging. Furthermore, it has become possible to track the dynamics of intracellular signaling of skeletal muscle cells or muscle progenitor cells in time and space by using advanced imaging techniques. In this review, we focus on the functional roles and regulatory mechanism of p38MAPK in skeletal muscle and its relation to the pathology in the context of dysregulation of skeletal muscle formation and regeneration.