Tricyclic antidepressants have been used to manage pain for several decades, and are superior treatments for some patients suffering from neuropathic pain. Unfortunately, older antidepressants have dose-limiting side effects that can lead to drug intolerance. The most common are anticholinergic side effects, although some patients experience sexual dysfunction. Cognitive impairment, sedation, and orthostatic hypotension also are relatively common. Taking an overdose of tricyclic antidepressants can be lethal in overdose. Several weeks of therapy may be required before antinociception occurs, but tricyclic antidepressants in optimal doses appear to be the most effective treatment for neuropathic pain; this is supported by systematic reviews comparing them with other agents. Newer medications such as atypical antidepressants and anticonvulsants may be overtaking older antidepressants, but they should not be overlooked as important options for the management of pain.