Some monoamine-uptake inhibitors are among first-line treatments for specific chronic pain conditions. It concerns tricyclic antidepressant drugs, such as amitriptyline or nortriptyline, and the more selective serotonergic and noradrenergic reuptake inhibitors, such as duloxetine. They are recommended for treating neuropathic pain, which is pain caused by a lesion or disease of the somatosensory nervous system, and fibromyalgia, which is a chronic widespread pain. Clinically, their action on pain was proposed to be independent from the one on depression. Research in animal models provided some understanding of the pain-relieving mechanism. The noradrenergic component of monoamine-uptake inhibitors appears to be critical, with the therapeutic effect likely involving targets at peripheral, spinal and supraspinal levels. At least two independent mechanisms would contribute to pain relief. One is spinal, relying on the recruitment of aminergic descending controls of pain, with a downstream key role of the α2 adrenergic receptors; the other may require more sustained treatment and relies on the noradrenergic recruitment of β2 adrenergic receptors and a downstream anti-neuroimmune action. Both mechanisms require a functional endogenous opioid system. These insights, however, focused on the sensory component of pain, and the contribution of the supraspinal action of antidepressant drugs needs to be explored in detail.