Whereas most pain due to cancer can be relieved with relatively simple methods using oral analgesics, as suggested by WHO guidelines, some patients may have difficult pain situations that require more complex approaches. It is estimated that 10-20 % of cancer patients suffer from pain that is not easily relieved. There are a number of factors that may reduce the efficacy of opioids in the management of cancer pain. Neuropathic pain (NP) and breakthrough pain (BP), especially of the incident subtype, have been identified as challenges for clinicians. In several prognostic studies, these two mechanisms were associated with limited positive outcomes compared with other syndromes. Opioid-induced hyperalgesia has recently been described as representing a challenge for physicians in the clinical setting. The global response to opioids, including the development of adverse effects, typically varies by individual and is likely genetically determined. Moreover, clinical evidence suggests that different opioids may produce different effect profiles, and so it is more appropriate to consider the response to each individual opioid rather than general opioid response. This paper will review both pharmacological and procedural mechanisms and treatments of these difficult pain syndromes.