Cell–cell signaling is essential for the functioning of the nervous, neuroendocrine and immune systems. Crucial for these processes are small, rapidly diffusible messengers including catecholamines (epinephrine, norepinephrine and dopamine), indoles (serotonin and melatonin), histamine, acetylcholine and nitric oxide. In this article, we show that the evolutionary history of most genes encoding enzymes involved in the metabolism of these messengers is best described by scenarios that include horizontal gene transfer (HGT) from bacteria, with some transfers occurring after the divergence of animals from fungi. The acquisition of bacterial genes via HGT seems to have had the essential role of extending existing biochemical pathways to yield the messengers. The possible relatively late HGT of some signaling enzymes contrasts with the apparent acquisition of central metabolic pathway enzymes early in eukaryotic evolution from the proto-mitochondrial endosymbiont.