Advanced breast cancer responds to a range of cytotoxic agents, but resistance always develops. Understanding the mechanisms of resistance may provide new therapeutic options. There are several major groups of resistance mechanisms. 1) The multidrug resistant phenotype. This is due to a membrane pump that can extrude a wide range of anticancer drugs--the P-glycoprotein. It is inhibited by a range of clinically used calcium channel blockers such as nifedipine and verapamil. Several other membrane proteins of 180 KD, 170 KD, 300 KD and 85 KD have been reported and are associated with MDR. 2) Glutathione transferences and detoxification mechanisms. These are a multigene family of enzymes that conjugate glutathione to chemically reactive groups. There are 3 major groups of enzymes--acidic, basic and neutral. They have been implicated in resistance to doxorubicin, melphalan cisplatinum chlorambucil and other alkylating agents. Other protecting systems include metallothionein and selenium dependent glutathione peroxidase. HSP27 confers doxorubicin resistance. 3) Topoisomerase II. DNA topoisomerases are involved in several aspects of DNA metabolism in particular genetic recombination, DNA transcription, chromosome segregation. They are a target for doxorubicin, mitoxantrone, VP16. Low levels of expression are associated with resistance. However, it is oestrogen inducible and this may be of therapeutic value. A novel topo IIb which is more drug resistant has been reported. 4) DNA repair. A score or more of genes are involved in the repair of DNA damage by drugs and radiation. Defective DNA repair may predispose to cancer of the breast and be responsible for adverse radiation reactions. Enhanced repair has been shown to be a mechanism of cisplatinum resistance. Several genes are inducible by DNA damage and may confer resistance e.g. A45. 5) Drug activation. Mitomycin C as well as cyclophosphamide and VP16 require activation for their effects. Low levels of cytochrome p450 reductase are associated with MMC resistance.