G-protein-coupled receptors (GPCRs), which are encoded by > 300 genes in the human genome, are by far the largest class of targets for modern drugs. These macromolecules display inherent adaptability of function, which is partly due to the production of different forms of the receptor protein. These are commonly called ‘isoforms’ or ‘splice variants’ denoting the molecular process of their production/ assembly. Not all GPCRs are expressed as splice variants, but certain subclasses of 5-HT receptors are for example, the 5-HT4 and 5-HT7 receptors. There are at least 11 human 5-HT4 and three h5-HT7 receptor splice variants. This review describes their discoveries, nomenclature and structures. The discovery that particular splice variants are tissue specific (or prominent) has highlighted their potential as future drug targets. In particular, this review examines the functional relevance of different 5-HT4 and 5-HT7 receptor splice variants. Examples are given to illustrate that splice variants have differential modulatory influences on signalling processes. Differences in agonist potency and efficacies and also differences in desensitisation rates to 5-HT occur with both 5-HT4 and 5-HT7 receptor splice variants. The known and candidate signalling systems that allow for splice variant specific responses include GPCR interacting proteins (GIPs) and GPCR receptor kinases (GRKs) which are examined. Finally, the relevance of 5-HT receptor splice variants to clinical medicine and to the pharmaceutical industry is discussed.