Oxaliplatin is a chemotherapeutic agent effective against advanced colorectal cancer. Unlike with other platinum-based agents, the main side effect of oxaliplatin is polyneuropathy. Oxaliplatin-induced polyneuropathy (OIPN) has a unique profile, which can be divided into acute and chronic neurotoxicity. Early identification of the neurotoxicity and alterations in dose or schedule for the medication could prevent the development of chronic symptoms, which, once established, may take many months or years to resolve or even persist throughout life with a substantial effect on quality of life. There is no doubt that the use of pharmacogenomic methods to identify genetic bases of interindividual differences in drug response has led to what is called tailoring treatment. Yet there are some challenges regarding the application of these differences. Many efforts have been made to prevent or treat OIPN. Better understanding of the mechanisms underlying the acute and chronic forms of OIPN will be a key component of future advances in the prevention and treatment of OIPN. The aim of this review is to highlight the clinical presentation, assessment, and management of OIPN, as well as the underlying pathophysiologic and pharmacogenomic background.