Since prehistorical times humans have relieved anxiety by chemical means. Psychiatry made use of a variety of sedatives in the 19th century, but the development of barbiturates one hundred years ago defined a new mainstream that was further profoundly changed with the serendipitous discovery of 1,4-benzodiazepines. Benzodiazepine tranquillizers not only provide rapid relief of anxiety but exert also an anticonvulsant, myorelaxant and hypnotic effect. While relatively safe as single treatment, drug interactions, especially with ethyl alcohol, are potentially dangerous, and overall sedation as well as the capacity to produce dependence limit relaying on these compounds. Reduction in benzodiazepine use has become possible owing to the rise of antidepressants such as selective serotonin reuptake inhibitors and serotonin and noradrenaline reuptake inhibitors that have become the first-line treatments of anxiety disorders. The 2013 Oswald Schmiedeberg Lecture described recent attempts to develop principally novel anxiolytics, with particular focus on neuropeptide systems. Among promising approaches are the selective modulators of GABA- and glutamatergic and endocannabinoid neurotransmission as well as neuropeptide receptor antagonists and multitarget drugs that are ushering in the era of more personalized pharmacotherapy.