The nucleation of many breast cancer research projects is the choice of an appropriate model to be used, and a central question to be addressed. Often, a human breast cancer cell line is chosen, and a selection of assays is then employed to test new anti-cancer agents, or to study some aspect of the biology of the disease. Here, we provide a guide for the selection of preclinical models of breast cancer, focusing on commonly chosen cell lines, including MDA-MB-231, MCF-7, BT-474, T47D, and ZR75.1. Important criteria to consider include, among others, the ease of growth of the cells, whether they can form organotypic cultures, their amenability for drug screening assays, whether they are part of the NCI 60 cancer cell line panel, and their array of expression of oncogenes and tumor suppressor genes. Critical to the success of a project may also be whether the model can grow in vivo, and if it can metastasize. The ideal preclinical model is therefore one that permits multiplex in vitro screens as well as complex, orthotopic, animal models that replicate aspects of late stage disease. Additional criteria to consider include proprietary restrictions of some cell lines, which may later hamper drug development, and whether the models comply with institutional guidelines, as well as the possibility of incorporating molecular markers that allow for the in vivo non-invasive monitoring of disease. We provide practical examples to illustrate the challenges and the solutions to developing breast cancer projects, including studies on the treatment of metastatic disease using metronomic chemotherapy, either alone or in combination with anti-Her-2 targeting strategies, such as trastuzumab and pertuzumab.