In recent years, oxaliplatin-based chemotherapy protocols, particularly oxaliplatin in combination with infusional 5-fluorouracil/leucovorin (FOLFOX or FUFOX), have emerged as the standard of care in first- and second-line therapy of advanced-stage colorectal cancer. Although oxaliplatin by itself has only mild hematologic and gastrointestinal side effects, its clinically dominating toxicity affects the peripheral sensory nervous system in the form of 2 distinct types of neurotoxicity: (1) a unique, frequent, acute sensory neuropathy that is triggered or aggravated by exposure to cold but at the same time is rapidly reversible without persistent impairment of sensory functions; (2) the dose-limiting toxicity of oxaliplatin, a cumulative, chronic sensory neurotoxicity that resembles that of cisplatin with the important difference of its being more rapidly and completely reversible. This chronic sensory neurotoxicity is highly predictable, being closely associated with the cumulative dose of oxaliplatin that is administered. Various strategies have been proposed to prevent or treat oxaliplatin-induced neurotoxicity. The stop-and-go concept uses the predictability and reversibility of neurologic symptoms to allow patients to stay on an oxaliplatin-containing first-line therapy for a prolonged period. Several neuromodulatory agents such as calcium-magnesium infusions; antiepileptic drugs like carbamazepine, gabapentin, and venlafaxine; amifostine; a-lipoic acid; and glutathione have demonstrated some activity in the prophylaxis and treatment of oxaliplatin-induced acute neuropathy. However, randomized trials demonstrating a prophylactic or therapeutic effect on oxaliplatin's cumulative neurotoxicity are still lacking. 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. This is of increasing importance, because the addition of bevacizumab to FOLFOX will conceivably further prolong the progression-free survival achieved with FOLFOX so that neurotoxicity and not tumor progression could become the dominating treatment-limiting issue in the first-line therapy of advanced colorectal cancer.