The serotonin 3 (5-HT₃) receptor is a ligand gated ion channel unlike the other 5-HT receptors which are G protein coupled receptors. The functional 5-HT₃ receptor forms a pentamer of five symmetrically arranged subunits surrounding a central pore. The 5-HT(3A) subunit was first identified at a molecular level and can form functional homomers or heteromers with the 5-HT(3B) subunit. Recently, three new 5-HT₃ subunits have been discovered and these can also form functional heteromers with the 5-HT(3A) subunit. In addition, splice variants of the 5-HT₃ subunits have also been reported. These findings have markedly increased the complexity of the 5-HT₃ receptor and may form part of the explanation of unresolved differences between studies investigating 5-HT₃ receptor function in cell lines compared with native tissues. In this review we discuss the properties of the different subunits and their distribution to determine if they contribute to functional changes in the 5-HT₃ receptor. Several recent pharmacogenomic studies have revealed single nucleotide polymorphisms (SNPs) and other variations in the different 5-HT₃ receptor subunits that are associated with various clinical conditions. We discuss the implications of these findings with respect to drug design and tailored pharmacogenomic therapies.