Up to 70% of patients with cancer should be expected to experience pain during the cancer illness. This is clearly more likely as disease progresses. The World Health Organisation (WHO) cancer pain guidelines remain the key to following a simple and systematic approach to cancer pain control in approximately 80% of patients. This approach was never intended to be used in isolation of various non-pharmacological approaches, including tumouricidal therapies. However, lateral thought when managing challenging cancer-related pain becomes even more critical. This paper reviews the approach to the approximately 20% of patients who do not respond to the standard WHO three-step analgesic ladder approach and of course, by definition this means in practice those patients with severe pain which is not controlled by morphine or alternative strong opioids. Such cancer pain can be broadly categorised as opioid irrelevant pain, opioid partially responsive pain, opioid unresponsive pain or pain resulting from excess opioid.