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-HT3A subunit was first identified at a molecular level and can form functional homomers or heteromers with the 5-HT3B subunit. Recently, three new 5-HT3 subunits have been discovered and these can also form functional heteromers with the 5-HT3A 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.