Receptors involved in intercellular communication at the cell surface share the capacity to desensitize through molecular and cellular mechanisms. Cellular desensitization is a rapid and dynamic process whereby membrane receptors internalize in response to an excess of agonists. The internalized receptors may recycle rapidly or undergo down-regulation when following a degradative pathway. However, receptor internalization does not necessarily mean degradation; it also represents the initial step of a retrograde signalling system whereby an "interiorized" message, the ligand-receptor complex, can be transported in contrast to second messengers, along axons or in the cytoplasm leading to long-term effects in the nucleus. Such "third messengers" have to undergo nuclear translocation to serve as transcriptional regulators in the control of gene expression. The "third messengers" are thus cytoplasmic proteins, including the receptor itself, which may be associated with internalized vesicles and released by mechanisms which have not yet been elucidated. They represent already good targets for the development of new drugs, and multi-targeting and synergistic approaches are likely to increase their usefulness.