Mitogen-activated protein kinase (MAPK) signaling pathways are involved in multiple important cellular responses. To activate their downstream protein kinases by phosphorylation is a crucial manner for MAPK family members to fulfill their physiological functions. Downstream of MAPKs, there exist three structurally related MAPK-activated protein kinases (MAPKAPKs or MKs), i.e., MK2, MK3 and MK5. Once upon activated by MAPKs, MKs signal to different cellular targets, to regulate gene expression at the levels of transcription and translation, control cytoskeleton remodelling and cell cycle, and mediate cell migration and embryonic development. Recently, based on the gene knockout studies, the function divisions among different MK subfamily members are gradually clear, leading to tremendous advancements of our knowledge on MKs.