The multidrug resistance-associated protein (MRP) mediates the cellular excretion of many drugs, glutathione S-conjugates (GS-X) of lipophilic xenobiotics and endogenous cysteinyl leukotrienes^1–5. Increased MRP levels in tumor cells can cause multidrug resistance (MDR) by decreasing the intracellular drug concentration. The physiological role or roles of MRP remain ill-defined, however. We have generated MRP-deficient mice by using embryonic stem cell technology. Mice homozygous for the mrp mutant allele, mrp^−/−, are viable and fertile, but their response to an inflammatory stimulus is impaired. We attribute this defect to a decreased secretion of leukotriene C₄ (LTC₄) from leukotriene-synthesizing cells. Moreover, the mrp^−/− mice are hypersensitive to the anticancer drug etoposide. The phenbtype of mrp^−/− mice is consistent with a role for MRP as the main LTC₄-exporter in leukotriene-synthesizing cells, and as an important drug exporter in drug-sensitive cells. Our results suggest that this ubiquitous⁶ GS-X pump^7,8 is dispensable in mice, making treatment of MDR with MRP-specific reversal agents potentially feasible.