Endothelin-1 (ET-1) is a 21-amino-acid peptide, derived from vascular endothelial cells, with potent vasoconstrictor activity. ET-1 has been implicated in diverse physiological or pathological processes^,, including the vascular changes associated with sepsis^,,,. However, the factors that regulate ET-1-associated toxicity during bacterial infections, or in other settings, are not fully understood^,,,. Both the pathology associated with certain allergic and autoimmune disorders^,, and optimal host defence against bacterial and parasitic infections^,, are mediated by mast cells. In vitro, mast cells can produce ET-1 (ref. ), undergo ET-1-dependent and endothelin-A receptor (ET_A)-dependent activation^,, and release proteases that degrade ET-1 (ref. ). Although the potential relationships between mast cells and the ET-1 system thus may be complex, the importance of interactions between ET-1 and mast cells in vivo is obscure. Here we show that ET_A-dependent mast-cell activation can diminish both ET-1 levels and ET-1-induced pathology in vivo, and also can contribute to optimal survival during acute bacterial peritonitis. These findings identify a new biological function for mast cells: promotion of homeostasis by limiting the toxicity associated with an endogenous mediator.