Pathological pain, such as inflammatory and neuropathic pain, is an expression of neural plasticity. Mitogen-activated protein kinases (MAPKs) play an important role in neural plasticity via post-translational, translational and transcriptional regulation. Under conditions of tissue and nerve damage, extracellular signal-regulated kinase (ERK) and p38 MAPK can be activated by nociceptive activity and inflammatory mediators in primary sensory neurons in the peripheral nervous system, and spinal cord neurons and glia in the central nervous system. Activation of ERK in dorsal horn neurons is nociceptive-specific and suppressed by several analgesics, and therefore has potential for the development of an assay to test the efficacy of new analgesics. Inhibition of ERK or p38 alleviates inflammatory pain and neuropathic pain in animal models. Development of specific inhibitors for these two MAPKs may lead to new therapies for pathological pain.