This review covers recent developments in the cellular neurophysiology of retrograde signaling in the mammalian central nervous system. Normally at a chemical synapse a neurotransmitter is released from the presynaptic element and diffuses to the postsynaptic element, where it binds to and activates receptors. In retrograde signaling a diffusible messenger is liberated from the postsynaptic element, and travels "backwards" across the synaptic cleft, where it activates receptors on the presynaptic cell. Receptors for retrograde messengers are usually located on or near the presynaptic nerve terminals, and their activation causes an alteration in synaptic transmitter release. Although often considered in the context of long-term synaptic plasticity, retrograde messengers have numerous roles on the short-term regulation of synaptic transmission. The focus of this review will be on a group of molecules from different chemical classes that appear to act as retrograde messengers. The evidence supporting their candidacy as retrograde messengers is considered and evaluated. Endocannabinoids have recently emerged as one of the most thoroughly investigated, and widely accepted, classes of retrograde messenger in the brain. The study of the endocannabinoids can therefore serve as a model for the investigation of other putative messengers, and most attention is devoted to a discussion of systems that use these new messenger molecules.