Oxaliplatin has become an integral part of various chemotherapy protocols, and in advanced colorectal cancer in particular. While oxaliplatin has only mild hematologic and gastrointestinal side effects, its dose-limiting toxicity is a cumulative sensory neurotoxicity that resembles that of cisplatin with the important difference of a more rapid and complete reversibility. The reversibility of neurotoxicity has been assured in long-term follow-up of patients who have received adjuvant oxaliplatin-based chemotherapy. In addition, oxaliplatin causes a very unique, but frequent, acute sensory neuropathy that is triggered or aggravated by exposure to cold but is rapidly reversible, without persistent impairment of sensory function. Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. The "Stop-and-Go" concept uses the reversibility of neurologic symptoms to aim at delivering higher cumulative oxaliplatin doses as long as the therapy is still effective. Several neuromodulatory agents such as calcium-magnesium infusions, antiepileptic drugs like carbamazepine or gabapentin, amifostine, alpha-lipoic acid, and glutathione have shown promising activity in prophylaxis and treatment of oxaliplatin-induced neurotoxicity. However, larger confirmatory trials are still lacking so that, to date, no evidence-based recommendation can be given for the prophylaxis of oxaliplatin-induced neurotoxicity. The predictability of neurotoxicity associated with oxaliplatin-based therapy should allow patients and doctors to develop strategies to manage this side effect in view of the individual patient's clinical situation.