Traditionally, biomedical research in the field of pain has been conducted with male animals and subjects. Over the past 20–30 yr, it has been increasingly recognized that this narrow approach has missed an important variable: sex. An ever-increasing number of studies have established sex differences in response to pain and analgesics. These studies have demonstrated that the differences between the sexes appear to have a biological and psychological basis. We will provide brief review of the epidemiology, rodent, and human experimental findings. The controversies and widespread disagreement in the literature highlight the need for a progressive approach to the questions involving collaborative efforts between those trained in the basic and clinical biomedical sciences and those in the epidemiological and social sciences. In order for patients suffering from acute and/or chronic pain to benefit from this work, the approach has to involve the use or development of clinically relevant models of nociception or pain to answer the basic, but complex, question. The present state of the literature allows no translation of the work to our clinical decision-making.