The concept that 5-hydroxytryptamine (5-HT; serotonin) is involved in the emetic reflex was revealed using drugs that interfere with its synthesis, storage, release and metabolism ahead of the discovery of selective tools to modulate specific subtypes of receptors. This review comprehensively examines the fundamental role of serotonin in emesis control and highlights data indicating association of 5-HT 1–4 receptors in the emetic reflex, whilst leaving open the possibility that 5-HT 5–7 receptors may also be involved. The fact that each receptor subtype may mediate both emetic and anti-emetic effects is discussed in detail for the first time. These discussions are made in light of known species differences in emesis control, which has sometimes affected the perception of the translational value of data in regard to the development of novel anti-emetic for use in man.