All the classical transmitter ligand molecules evolved at least 1000 million years ago. With the possible exception of the Porifera and coelenterates (Cnidaria), they occur in all the remaining phyla. All transmitters have evolved the ability to activate a range of ion channels, resulting in excitation, inhibition and biphasic or multiphasic responses. All transmitters can be synthesised in all three basic types of neurones, i.e. sensory, interneurone and motoneurone. However their relative importance as sensory, interneurone or motor transmitters varies widely between the phyla. It is likely that all neurones contain more than one type of releasable molecule, often a combination of a classical transmitter and a neuroactive peptide. Second messengers, i.e. G proteins and phospholipase C systems, appeared early in evolution and occur in all phyla that have been investigated. Although the evidence is incomplete, it is likely that all the classical transmitter receptor subtypes identified in mammals, also occur throughout the phyla. The invertebrate receptors so far cloned show some interesting homologies both between those from different invertebrate phyla and with mammalian receptors. This indicates that many of the basic receptor subtypes, including benzodiazepine subunits, evolved at an early period, probably at least 800 million years ago. Overall, the evidence stresses the similarity between the major phyla rather than their differences, supporting a common origin from primitive helminth stock.