Over half of all drugs available today act by interacting with membrane proteins, and there is intense interest in understanding these proteins at the molecular level. Unfortunately, this large class of proteins is only poorly understood at the biochemical and structural level because membrane proteins are notoriously difficult to study. We are using both novel and established methods to study two membrane proteins that are involved in drug resistance. The first is a molecular pump called MsbA, which is able to transport a variety of drugs out of cells. Similar pumps are involved in multi-drug resistance, which is an important problem in cancer chemotherapy. The second is called MacB. This protein pumps antibiotics out from bacteria, contributing to the problem of microbial antibiotic resistance. Our studies on these proteins may lead to ways to counteract resistance mechanisms that reduce the efficacy of drugs.