Invertebrate receptors for the neurotransmitter serotonin (5-HT) have been identified in numerous species from diverse phyla, including Arthropoda, Mollusca, Nematoda and Platyhelminthes. For many receptors, cloning and characterization in heterologous systems have contributed data on molecular structure and function across both closely and distantly related species. This article provides an overview of heterologously expressed receptors, and considers evolutionary relationships among them, classification based on these relationships and nomenclature that reflects classification. In addition, transduction pathways and pharmacological profiles are compared across receptor subtypes and species. Previous work has shown that transduction mechanisms are well conserved within receptor subtypes, but responses to drugs are complex. A few ligands display specificity for different receptors within a single species; however, none acts with high specificity in receptors across different species. Two non-selective vertebrate ligands, the agonist 5-methoxytryptamine and antagonist methiothepin, are active in most receptor subtypes in multiple species and hence bind very generally to invertebrate 5-HT receptors. Future challenges for the field include determining how pharmacological profiles are affected by differences in species and receptor subtype, and how function in heterologous receptors can be used to better understand 5-HT activity in intact organisms.