The serotonin system plays an important role in the neural processing of anxiety. The involvement of the main inhibitory serotonergic receptor, the serotonin-1A (5-HT1A) subtype, in dysfunctional forms of anxiety has been supported by findings from a wide range of preclinical research and clinical trials, including treatment studies, genetic research, and neuroimaging data. The following article summarizes preclinical results with a focus on 5-HT1A receptor knockout and transgenic mice as genetic models of anxiety. Behavioral, autonomic, and endocrinological changes in these mice are reported. This article also presents genetic polymorphisms in humans associated with increased anxiety scores and pharmacological data focused on 5-HT1A receptor agonists and antagonists. Furthermore, molecular neuroimaging results are presented. Recent positron emission tomography (PET) studies have reported reduced 5-HT1A receptor binding in patients with panic disorder and social anxiety disorder, but not in posttraumatic stress disorder. In healthy subjects, increased anxiety scores might be associated with lower 5-HT1A receptor binding. This overview of preclinical and clinical data provides strong evidence for the key role of the 5-HT1A receptor in the serotonergic dysregulation of anxiety disorders.