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By administering systemic therapy before definitive local surgery in patients with large operable breast cancers (T2, T3, N0, N1, M0) an in vivo human tumour model system has been devised which allows direct objective assessment of response to systemic therapy in the individual patient. Response was assessed following 12 weeks of systemic therapy by linear regression analysis of changes in tumour volume measured at weekly intervals. Definitive locoregional (mastectomy n = 82, wide local excision n = 6) was performed on completion of systemic therapy (3-6 months). Responses to both endocrine (n = 61) and cytotoxic therapies (n = 47) have been studied. Twenty-seven patients received both forms of treatment. A biopsy of the tumour (fine-needle aspirate and open wedge biopsy) was performed prior to initiating systemic therapy. Using the human tumour model system it has been possible to evaluate the predictive value for response of several pretreatment tumour indices. These have included tumour ER concentration assayed by either dextran-coated charcoal method of immunocytochemical staining (ERICA), the activity of enzymes involved in local steroidogenesis i.e. tumour aromatase activity and peritumour fat 17B hydroxysteroid dehydrogenase activity, tumour grade and tumour ploidy. By obtaining a biopsy of tumour and after systemic therapy it was also possible to determine the effects of systemic therapy on these potential indices of response. Response was observed in 24 (39%) of the 61 patients who received endocrine therapy and 34 (72%) of the 47 patients who received cytotoxic therapy. Of the predictive indices examined within this study only ER concentration and possibly tumour aromatase activity have been shown to be of any value in relation to response to endocrine therapy and aromatase inhibitors respectively. The other parameters studied have been uniformly disappointing in their prophetic value. When systemic therapy is given as the preferred first line therapy however response to therapy can be assessed on an individual basis and hence allow determination of appropriate systemic therapy. By using this principal a selective protocol for adjuvant systemic therapy has been devised. Endocrine therapy should be reserved for patients with tumours of ER concentration of ≥ 20 fmol/mg cytosol protein. Patients with ER-poor/negative tumours or those which fail to respond to endocrine therapy should receive cytotoxic therapy. Using this protocol the overall survival rate at 4 years was 77% (+ /- 5%) with 83% (+ /- 4%) remaining free from local relapse. The treatment policy outlined within this paper is now being tested against orthodox management by controlled randomised trial.