Researching the functions of serotonin, or 5-hydroxytryptamine (5-HT), in the gut has helped define new 5-HT receptors, increased the understanding of the side effects of numerous drugs and, via development of drugs, brought relief to millions of people suffering from disorders such as gastroparesis, dyspepsia, constipation, diarrhoea, irritable bowel syndrome and cancer. However, safety issues associated with alosetron and tegaserod (key drugs that modulate 5-HT function) have brought 5-HT and gastrointestinal research to a crossroad--is it now too hard to develop drugs in this area or is there a way forward? In this review, I describe the background to 5-HT in gastrointestinal physiology and disease, and the actions of drugs that interact with 5-HT3 and 5-HT4 receptors. Future research directions include modulating 5-HT availability by inhibition of tryptophan hydroxylase, understanding the functions of receptors such as 5-HT2B, 5-HT7 and the recently described 5-HT3-receptor subunits, and investigating how receptors activated by other products of tryptophan catabolism interact with gastrointestinal functions of 5-HT.