The abundance of mast cells in human dermis, together with their ability to release a variety of vasoactive and pro-inflammatory mediators following cross-linkage of their cell-surface receptors for IgE, enables these cells to provide an effective defence mechanism within this organ. A similar defensive function is attributed to mast cells of other human organs such as intestine and lung which are in contact with the external environment and therefore susceptible to infiltration by foreign allergens and micro-organisms. However, mast cells of the skin apparently differ from those present in lung and intestine in being activated for histamine release by a variety of endogenous neuropeptides which stimulate the rapid release of histamine in the virtual absence of eicosanoids. This would provide a mechanism of neurogenic control of a variety of homeostatic functions such as blood flow, angiogenesis and fibroblast proliferation. Such processes would aid in the remodelling of tissue during wound healing, and increased numbers of mast cells have been noted around healing wounds of rat skin and areas of developing fibrosis. Neuropeptides modulate the activity of a variety of immuno-competent leucocytes including macrophages, monocytes and lymphocytes. The findings that skin mast cells are activated by neuropeptides suggest that these cells may also be included amongst those involved in neuro-immune interactions. Activation of skin mast cells by non-immunological stimuli may contribute to the aetiology of some forms of skin disease. Patients with chronic idiopathic urticaria appear to have enhanced vascular responsiveness to intradermal injections of the histamine liberator codeine suggesting that this disease may involve hyper-responsiveness of their mast cells to endogenous non-immunological stimuli. The findings of large increases in histamine accompanied by small increases in PGD2 in venous effluent of thermally challenged limbs of patients with cold- or heat-induced urticaria may suggest that their mast cells had been activated by a non-immunological stimulus. However, the interpretation of results gained using such relatively complex in-vivo systems are difficult, as the cellular origin of the detected mediators is by no means clear. However, it is hoped that in the future the alliance of newly developed in-vitro techniques to investigate mast cell function together with in-vivo methods to investigate their interaction with elements in their tissue environment will greatly increase our understanding of the role of the human skin mast cell in health and disease.