Mitogen-activated protein kinases (MAPKs) are a group of serine/threonine specific, proline directed, protein kinases which are activated by a wide spectrum of extracellular stimuli. MAPK activation is achieved through kinase cascades, which include a MAPK kinase (MAPKK or MEK) and a MAPKK/MEK kinase (MAPKKK/MEKK). These cascades serve as information relays, connecting cell-surface receptors to specific transcription factors and other regulatory proteins, thus allowing extracellular signals to regulate the expression of specific genes. Genetic and biochemical analyses have revealed many tiers in the regulation of the activities of MAPKs, as well as different routes that lead to the activation of an individual MAPK. An emerging topic of great interest is the basis for specificity in the activation of individual MAPKs and their ability to recognize their substrates.