In multicellular organisms, many molecules transmit signals between cells to pass information. These signals vary in complexity and include small peptides, nucleotides, steroids, fatty acid derivatives, and dissolved gases such as nitric oxide. Some signaling molecules diffuse through the plasma membrane to act locally between neighboring cells or travel long distances. Others remain attached to the cell surface, transmitting information to other cells only when they make contact. In some instances, special processing, such as proteolytic cleavage, may be required to release the extracellular domains of transmembrane signaling proteins. For example, peptide and protein signals are synthesized as inactive pre-pro-peptides in the rough endoplasmic reticulum, converted to pro-peptides by enzymatic cleavage, and further processed in the Golgi apparatus before being enzymatically activated in the transport vesicles destined for exocytosis.

Water-soluble or hydrophilic signals that cannot pass through the non-polar region of the plasma membrane or molecules that are too large to pass through the membrane bind the extracellular domain of cell-surface receptors. The group of molecules that bind the cell surface receptor is diverse. They primarily consist of amino acids that may be unmodified, modified into a derivative, or incorporated into peptides and proteins. For example, neurotransmitters like glutamate and GABA are amino acid signals synthesized and stored in vesicles by the neurons and released by exocytosis. Another neurotransmitter, dopamine, is derived from tyrosine.

Ions, particularly calcium, control critical cellular processes like muscle contraction, gene transcription, and apoptosis. They may either be involved in direct intracellular communication through gap junctions or may function as second messengers in intracellular signaling pathways. Nitric oxide, a gaseous signaling molecule known for its role in smooth muscle relaxation, diffuses directly across the plasma membrane. The drug nitroglycerin, which is used to treat heart disease, causes the release of nitric oxide. This causes blood vessels to dilate and restores blood flow to the heart.