Neuropathy is the chief dose-limiting side effect associated with the major classes of frontline cancer therapy drugs. Here the changes in behavioral responses of rats to cutaneous mechanical and thermal stimuli occurring following treatment with cisplatin and the changes in spinal neurophysiology accompanying the development of chemotherapy-induced hyperalgesia were explored. Systemic treatment with cisplatin induced changes in both mechanical and thermal cutaneous sensory withdrawal thresholds of Sprague-Dawley rats. High doses of chemotherapy produced hypoalgesia whereas lower doses produced hyperalgesia. Follow-up neurophysiological studies in rats with chemotherapy-induced hyperalgesia revealed that deep spinal lamina wide dynamic range neurons had significantly higher spontaneous activity and longer afterdischarges to noxious mechanical stimuli than wide dynamic range neurons in control rats; cisplatin administration was also associated with longer afterdischarges and abnormal wind-up to transcutaneous electrical stimuli. The hyperexcitability observed during cisplatin-induced hyperalgesia is very similar to that observed in rats with hyperalgesia produced following treatment with other very diverse types of chemotherapeutic agents and similar to that observed following specific types of direct nerve injury.