The serotonergic system plays a crucial role in regulating psychoemotional, cognitive and motor functions in the central nervous system (CNS). Among 5-HT receptor subtypes, 5-HT1A receptors have long been implicated in the pathogenesis and treatment of anxiety and depressive disorders. 5-HT1A receptors function as both presynaptic (autoreceptor) and postsynaptic receptors in specific brain regions such as the limbic areas, septum and raphe nuclei. 5-HT1A receptors negatively regulate cAMP-dependent signal transduction and inhibit neuronal activity by opening G-protein-gated inwardly rectifying potassium channels. The therapeutic action of 5-HT1A agonists and their mechanism in alleviating anxiety and depressive disorders have been well documented. In addition, recent studies have revealed new insights into the therapeutic role of 5-HT1A receptors in treating various CNS disorders, including not only depressive disorders (e.g., delayed onset of action and refractory symptoms), but also schizophrenia (e.g., cognitive impairment and antipsychotic-induced extrapyramidal side effects) and Parkinsons disease (e.g., extrapyramidal motor symptoms and L-DOPA-induced dyskinesia). These lines of evidences encourage us to design new generation 5-HT1A ligands such as 5-HT1A agonists with greater potency, higher selectivity and improved pharmacokinetic properties, and 5-HT1A ligands which combine multiple pharmacological actions (e.g., inhibition of serotonin transporter, dopamine D2 receptors and other 5-HT receptor subtypes). Such new 5-HT1A ligands may overcome clinical efficacy limitations and/or improve adverse reactions in current CNS therapies.