Ketamine has been used in the treatment of several pain syndromes, particularly those with a relevant neuropathic component. Sub-anesthetic doses of ketamine produce a potent analgesic effect, due to its inhibition of N-methyl-D-aspartate receptors and enhancement of descending inhibitory pathways. Its short-term analgesic effect is well-documented perioperatively, with an associated reduction in postoperative chronic pain and opioid consumption. Despite some evidence regarding its long-term benefits, the number of clinical studies is still limited. In addition to its analgesic effects, ketamine also possesses an anti-depressive action, which might be useful in the treatment of chronic pain patients. Several side effects have been described, the psychomimetic ones being the most relevant due to their impact on treatment adhesion. At present, co-administration of ketamine and benzodiazepines or α2-agonists facilitates its clinical application. Despite current evidence and increasing use, further investigation is still needed regarding its long-term safety profile and clearer risk-benefit analysis.