Neuropathic pain is the most common type of pain in neuropathy. In painful polyneuropathies the pain usually has a "glove and stocking" distribution. The pain may be predominantly spontaneous, e.g., with a burning, pricking, or shooting character or characterized by evoked pain such as mechanical or cold allodynia. In the clinical setting, the prevention of painful neuropathies and treatment of underlying neuropathy remains inadequate and thus symptomatic treatment of the pain and related disability needs to be offered. Most randomized, double-blind, placebo-controlled trials (RCTs) published in painful neuropathy have been conducted in patients with diabetes and to what extent a treatment which is found effective in painful diabetic polyneuropathy can be expected to relieve other conditions like chemotherapy- or HIV-induced neuropathy is unknown. Tricyclic antidepressants (TCAs), gabapentin, pregabalin, and serotonin noradrenaline reuptake inhibitors (SNRIs) are first drug choices. In patients with localized neuropathic pain, a topical lidocaine patch may also be considered. Second-line treatments are tramadol and other opioids. New types of treatment include botulinum toxin type A (BTX-A), high-dose capsaicin patches, and cannabinoids. Other types of anticonvulsant drugs such as lamotrigine, oxcarbazepine, and lacosamide have a more questionable efficacy in painful polyneuropathy but may have an effect in a subgroup of patients. Combination therapy may be considered in patients with insufficient effect from one drug. Treatment is usually a trial-and-error process and has to be individualized to the single patient, taking into account all comorbidities such as possible concomitant depression, anxiety, diseases, and drug interactions. Side-effects to antidepressants include dry mouth, nausea, constipation, orthostatic hypotension, and sedation. ECG should always be obtained prior to treatment with TCAs, which also should not be used in patients with cardiac incompensation and epilepsy. The most common side-effects of gabapentin and pregabalin are CNS-related side-effects with dizziness and somnolence. Peripheral edema, weight gain, nausea, vertigo, asthenia, dry mouth, and ataxia may also occur. Topical treatments are better tolerated due to lack of systemic side-effects but there is still limited evidence for the long-term efficacy of these drugs. With available drugs, the average pain reduction is about 20-30%, and only 20-35% of the patients will achieve at least 50% pain reduction, which stresses the need of a multidisciplinary approach to pain treatment.