Multidrug resistance is associated with the overexpression of P-glycoprotein, a membrane glycoprotein. The mechanism by which P-glycoprotein confers to cells the capacity to resist cytotoxic attack by structurally unrelated drugs has remained difficult to decipher. However, the recent functional expression of this group of proteins in the membrane of secretory vesicles from yeast mutants has allowed the systematic analysis of the parameters of drug transport by this protein. Proposed mechanisms of action of P-glycoprotein are discussed in this review by Stephan Ruetz and Philippe Gros.