Mutations resulting in a complex phenotype of cross-resistance and collateral-sensitivity are frequently observed in mammalian cell lines. A cell surface 170 000 dalton glycoprotein (P-glycoprotein) has been identified to be intimately associated with this multidrug resistance phenotype. We speculate that such mutations also occur in advanced cancers and play a major role in contributing to the non-response to combination chemotherapy. In this context, P-glycoprotein may be a useful molecular marker for diagnostic and therapeutic applications.