MSK1, and the related isoform MSK2, have become established as important regulators of immediate early gene transcription in response to signals that activate ERK1/2 and p38 signaling in mammalian cells. Though their ability to regulate the transcription of specific genes, they have further been shown to play important roles in both immunity and neuronal function. The chapters in this book summarize what in known about the molecular mechanism of MSK activation as well as MSK substrates and physiological functions. MSKs are unusual kinases in that they contain two distinct kinases domains in the same protein. The main function of the C-terminal kinase domain is to activate the N-terminal kinase domain, which then phosphorylates MSK’s substrates.