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Second messengers are intracellular signalling molecules released by the cell to trigger physiological changes such as proliferation, differentiation, migration, survival, and apoptosis. Secondary messengers are therefore one of the initiating components of intracellular signal transduction cascades. Examples of second messenger molecules include Cyclic AMP, Cyclic GMP, Inositol Triphosphate, Diacylglycerol, and Calcium. The cell releases second messenger molecules in response to exposure to extracellular signals - the First messengers. First Messengers are extracellular substances that include peptide hormones such as epinephrine, growth factors, and neurotransmitters such as serotonin. Because hormones and neurotransmitters typically comprise biochemically hydrophilic molecules, first messengers may not physically cross the phospholipid bilayer cell membrane to initiate changes within the cell directly. This functional limitation necessitates the cell to devise signal transduction mechanisms to transduce first into second messengers, so that the extracellular signal may be propagated intracellularly. An important feature of the second messenger signaling system is that second messengers may be coupled downstream to multi-cyclic kinase cascades to greatly amplify the strength of the original first messenger signal.For example, Ras.GTP signals link with the Mitogen Activated Protein Kinase (MAPK) cascade to amplify the allosteric activation of proliferative transcription factors like Myc and CREB.

Earl Wilbur Sutherland, Jr., discovered second messengers, for which he won the 1971 Nobel Prize in Physiology or Medicine. Sutherland saw that epinephrine would stimulate the liver to convert glycogen to glucose (sugar) in liver cells, but epinephrine alone would not convert glycogen to glucose. He found that epinephrine had to trigger a second messenger, cyclic AMP, for the liver to convert glycogen to glucose.The mechanisms were worked out in detail by Martin Rodbell and Alfred G. Gilman, who won the 1994 Nobel prize.

Secondary messenger systems can be synthesized and activated by enzymes, like the cyclases that synthesize cyclic nucleotides, or by opening of ion channels to allow influx of metal ions, like Ca2+ signaling. These small molecules bind and activate protein kinases, ion channels, and other proteins, thus continuing the signaling cascade.