Skeletal muscle development is regulated by extracellular growth factors that transmit largely unknown signals into the cell affecting the muscle-transcription program. One intracellular signaling pathway activated during the differentiation of myogenic cell lines is p38 mitogen-activated protein kinase (MAPK). As a result of modifying the activity of p38 in myoblasts, the pathway proved essential for the expression of muscle-specific genes. P38 affects the activities of transcription factors from the MyoD and MEF2 families and participates in the remodeling of chromatin at specific muscle-regulatory regions. P38 cooperates with the myogenic transcription factors in the activation of a subset of late-transcribed genes, hence contributing to the temporal expression of genes during differentiation. Recent developmental studies with mouse and Xenopus embryos, substantiated and further extended the essential role of p38 in myogenesis. Evidence exists supporting the crucial role for p38 signaling in activating MEF2 transcription factors during somite development in mice. In Xenopus, p38 signaling was shown to be needed for the early expression of Myf5 and for the expression of several muscle structural genes. The emerging data indicate that p38 participates in several stages of the myogenic program.