The ERK, p38MAPK, JNK mitogen-activated protein kinases (MAPKs) are intracellular signaling pathways that play a pivotal role in many essential cellular processes such as proliferation and differentiation. These cascades are activated by a large variety of stimuli and display a high degree of homology. So far, seven MAPK isoforms have been invalidated in mice leading to the discovery of their important functions in development and differentiation. As we could expect because of their multiple and specific properties in vitro, knockout (KO) of MAPK pathways leads to distinct phenotypes in mice. Surprisingly, into a given cascade, KOs of the various isoforms assign specific non-redundant biological functions to each isoform, without compensation by the others. These results emphasize the notion that, although initiated by the same external stimuli, these intracellular cascades activate kinase isoforms each with its own specific role.