Prostaglandin E2 (PGE2) is a prostanoid fatty acid derivative of arachidonic acid whose synthesis can be blocked by corticosteroids or by nonsteroidal anti-inflammatory drugs (NSAIDs). It is produced by a wide variety of tissues and is elevated in many bodily fluids during inflammation. PGE2 interacts with EP1, 2, 3, and 4 receptors to induce a complex range of effects. In the kidney, this includes stimulation of renin release and both promotion and inhibition of salt and water absorption. PGE2 can promote either smooth muscle relaxation or contraction. PGE2 is important in normal joint physiology and is a principal mediator of the inflammatory response to tissue damage. PGE2 sensitizes peripheral nociceptive nerves and exaggerates inflammatory and neuropathic pain by direct inhibition of spinal cord glycinergic neurotransmission. PGE2 also plays a role in hippocampal synaptic plasticity and febrile responses. PGE2 activity is linked to the synthesis and release of several hormones and the fetal hypothalamus-pituitary-adrenal axis. PGE2 also stimulates tumor cell proliferation and differentiation as well as tumor-associated neovascularization.