p44/42 MAPK, also known as extracellular signal-regulated kinases 1 and 2 (ERK1/2), are a subfamily of the mitogen-activated protein kinases (MAPK) family. They are activated by a wide range of extracellular stimuli, including growth factors, cytokines, and environmental stress signals. The activation of p44/42 MAPK involves a cascade of phosphorylation events, starting from MAPK kinase kinase (MAPKKK), through MAPK kinase (MAPKK), and finally leading to the activation of p44/42 MAPK. Upon activation, p44/42 MAPK phosphorylate and activate specific MAPK-activated protein kinases (MAPKAPKs), such as members of the RSK, MSK, or MNK families, as well as MK2/3/5. These kinases further amplify the signal and mediate the biological processes regulated by different MAPKs. Mutations or dysregulation of the p44/42 MAPK pathway have been implicated in various diseases, including cancer, neurological disorders, and cardiovascular diseases.