Multidrug Resistance Protein (MRP) confers resistance to natural product drugs when overexpressed in cultured cells. It has also been detected in human tumors and in some cases, expression has been correlated with a poor response to chemotherapy. MRP is present in normal tissues where it probably functions as an active transporter of amphiphilic anions. It is also presumed to transport the drugs to which it confers resistance, but how and in what form has not been resolved. Unlike other members of the ATP Binding Cassette superfamily, MRP and several related proteins have three potential membrane spanning domains. The additional NH2-proximal domain in MRP contains five membrane spanning helices with an extracytosolic NH2-terminus and is essential for transport. Conserved features of gene organization and protein structure suggest that MRP and its related proteins share their ancestry with the cystic fibrosis conductance regulator.