There are undoubtedly several causes of painful peripheral neuropathy in cancer patients. Some mechanisms are directly attributable to the tumor; others lie with the therapy, be it surgery, radiation, or chemotherapy. Several animal models have been developed to study the pathophysiological mechanisms that contribute to neuropathic pain. These include inflammation-based models, nerve trauma-induced models, and chemotherapy-induced models of neuropathic pain. My colleagues and I recently identified abnormalities in mitochondrial structure and function in peripheral sensory fibers that are associated with neuropathic pain induced by common chemotherapeutic agents and that can be reversed by agents that enhance mitochondrial function. Our hope is that further identification and clarification of the pathophysiological mechanisms involved at the periphery will help us to develop new classes of medicines and treatment options.