Rottenberg et al (2007, 2008) showed that upregulation of drug efflux pumps is the most prevalent mechanism of acquired resistance to conventional and targeted therapies for mammary tumours arising in the K14cre;Brca1F5–13/F5–13;Trp53F2–10/F2–10 mouse model. Currently, the treatment responses in this K14cre;Brca1F/F;Trp53F/F mouse model are being studied in a P-glycoprotein-deficient background to unravel P-glycoprotein-independent mechanisms of drug resistance (Table 2). The gene discussed is ABCB1; the disease is breast cancer.