There are well-documented sex differences in the prevalence of various painful disorders. To comprehend the mechanisms underlying these differences requires an understanding of the molecular organisation and systems biology that are responsible for the pain experience. The pain system evolved to secure the survival of the animal under a variety of environmental constraints and needed to be flexible enough to compete against other behavioural needs and homeostatic demands. From the periphery to the cortex, mechanisms exist to facilitate or inhibit nociceptive signalling and it is this inherent plasticity that is thought to be perturbed in chronic pain states. There is limited evidence to suggest that polymorphisms or mutations in certain genes and gender can influence the pain experience but it seems likely that epigenetics and the influence of past experience are responsible for a substantial part of the variation between sexes and between individuals.