The protein p38α is a member of a family of molecules that transmit outside signals throughout the cell, thus allowing for an appropriate cell response, such as proliferation, differentiation, senescence, or death. Moreover, the participation of p38α in pathological conditions, like chronic inflammatory diseases and cancer, makes it a promising pharmacological target. In this regard, a complete picture of the activation mechanism of this protein is essential in order to design specific inhibitors that do not affect other processes.