Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common, potentially severe and dose-limiting adverse effect of cancer treatment; however, the effects of CIPN on the daily life of individuals are not completely understood. CIPN can be induced by several types of drugs that are widely used in the treatment of solid and hematological malignancies. Our knowledge of the mechanisms underlying CIPN is incomplete, but structural properties of the various neurotoxic compounds might contribute to variations in the pathogenetic mechanisms of damage, in addition to the type of neurotoxicity, severity of the clinical condition, and incidence of CIPN. No drugs capable of preventing the occurrence of CIPN or ameliorating its long-term course are available, and chemotherapy schedule modification is often required to limit its severity, which could potentially prevent patients from receiving the most effective treatment for cancer. Moreover, symptomatic therapy is often largely ineffective in reducing CIPN symptoms. In this Review, the mechanistic and clinical aspects of this unpredictable condition are considered, along with the controversial aspects of CIPN, including the onset mechanisms associated with the different drug types, assessment of the patient's condition, and the current status of neuroprotection and treatment options.