Pain that is poorly responsive to opioid analgesics is challenging for physicians who deal with cancer patients. Numerous factors may influence analgesic response during the course of the illness. These include changing nociception associated with disease progression, the appearance of intractable side effects, the development of tolerance, the presence of neuropathic pain, the temporal pattern, the effects produced by the production of opioid metabolites, and many others. These factors influence the delicate balance between pain relief and opioid toxicity that must be achieved in cancer patients with pain.