Although it is widely appreciated that patients can demonstrate highly variable responses to different opioid drugs, there have been few detailed descriptions of this phenomenon. To illustrate this variability, we present 5 patients, 4 with cancer pain and 1 with non-malignant pain, who underwent dose titration with more than 1 opioid and developed markedly different responses to each. In every case, dose escalation led to successful treatment with 1 opioid and to intolerable side effects without adequate relief with others. The existence of this individual variability in the response to different opioids has important implications for both clinical practice and current understanding of opioid pharmacology in man. It contradicts the view that any opioid is inherently more efficacious than any other, suggests that patients who fail to obtain adequate pain relief at maximally tolerated doses of 1 opioid may benefit from an alternative drug, and underscores the potential importance of genetic factors as a determinant of opioid response.