The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) has been implicated in the etiology or treatment of so many medical problems, including anxiety, depression, obsessive-compulsive disorder, schizophrenia, hypertension, stroke, migraine, and nausea. This chapter discusses the recent advancement in the research of serotonin. The 5-HT1 receptor is a high affinity binding site and is divided into four subgroups. In the central nervous system (CNS), the 5-HT1A receptor is broadly distributed, occurring as a somaldodendritic autoreceptor on 5-HT neurons. The 5-HT1A receptor has been widely implicated in anxiety and depression. The 8-OH-DPAT is the prototypical 5-HT1A agonist and in its radiolabeled form is used to characterize the 5-HT1A receptor. A growing body of evidence indicates that compounds in the arylpiperazine class have anxiolytic and antidepressant properties in humans. This effect is thought to be mediated by an inhibitory action on neurons and not simply a result of agonist induced hypothermia. Selective 5-HT1A antagonist remains elusive. While not selective, the most commonly used 5-HT1A antagonists are spiperone, propranolol, and pindolol. Although the 5-HT1B receptor is found in rats and mice, its presence has not been demonstrated in humans. Most agents that bind at the 5-HT1C receptor also bind at 5-HT2 receptors. Although it is not selective, ketanserin is the prototypical 5-HT2 receptor antagonist. There has been a longstanding interest in 5-HT2 antagonists for the prophylactic treatment of migraine. Despite the large amount of research aimed at discovering 5-HT3 receptor ligands, selective ligands have only recently become available. A large number of compounds have been prepared that bind at the 5-HT3 receptor as antagonists. Many of these compounds are clinically effective in reducing the nausea caused by radiation and chemotherapy cancer treatments.