Results of standard multimodality treatment for locally advanced breast cancer (LABC) are still disappointing, due to a persistent high risk of relapse and death with longer-term follow-up. Increasing knowledge of tumour immunology provides the basis for new strategies in clinical trial design. Chemotherapy reduces tumor mass and tumor-derived immunosuppressive factors and, at the same time, causes release of tumor antigens; thereby favouring immune activation. An intermediate high-dose chemotherapy schedule with doxorubicin and cyclophosphamide, in combination with granulocyte-macrophage colony stimulating factor (GM-CSF) has been developed. Long-term neoadjuvant application of this regimen may overcome the dysfunction of the immune system and help to eradicate the tumor. Furthermore, tumor-derived antiangiogenic factors might inhibit outgrowth of micrometastases. This review aims to discuss current experience with LABC treatment, taking into account therapeutic alternatives and biological concepts tested in an international phase III trial; the Spinoza Trial.