Patients with comorbid major depression and generalized anxiety disorder (GAD) tend to have a more severe and prolonged course of illness and greater functional impairment. GAD is one of the most common mental disorders in primary medical-care settings, and is associated with increased use of health services. Current theories on pathological anxiety fit a multifactorial epigenetic model that integrates early stressors, inherited and acquired vulnerabilities, and the risks of developing interrelated or coincidental somatic diseases. The tolerability profile of prescribed medication is an important consideration, particularly when long-term treatment is recommended. Distressing symptoms on stopping treatment are common with many classes of psychotropic drug, including selective serotonin reuptake inhibitor (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), and benzodiazepines. There is clearly room for improvement in the development of more efficacious and more acceptable pharmacological approaches to the management of this common, distressing, typically disabling, and often persistent anxiety disorder.