Dermatologists are only too aware of the significant role psychosocial stress plays in the exacerbation of skin disease; indeed, it is often the first precipitant patients mention when they attend outpatient clinics. Of late, research has focused on understanding the 'brain-skin' axis, a complex interplay between the nervous and immune systems and the skin. In particular, there is an evolving body of literature exploring the underlying pathophysiological mechanisms by which psychosocial stress influences skin homeostasis. This article provides a broad overview of the literature, emphasizing the importance of individual stress perception and summarizing the varied roles of the major cutaneous stress-response pathways. Both central [the hypothalamic-pituitary-adrenal (HPA) axis and the locus ceruleus-norepinephrine (LC-NE) sympathetic adrenomedullary system] and peripheral (the intracutaneous HPA axis and the release of mediators from peripheral sensory and autonomic nerves) pathways are discussed. Moreover, how activation of these pathways affects the skin's immune system, barrier function, wound healing and susceptibility to infection is reviewed. Although this field of research is rapidly expanding, several important questions remain unanswered, including: what is the precise role of mast cells in the cutaneous stress response?; what is the role of regulatory T-cells?; can therapeutic intervention be harnessed to prevent the stress-induced exacerbation of skin disease? It is anticipated that an improved understanding of the underlying mechanisms through which psychosocial stress affects the homeostasis of healthy skin will not only increase knowledge of the brain-skin axis but will also improve the holistic management of stress-responsive cutaneous disease.