Cancer stem cells are resistant to current chemotherapy and radiation regimens available for breast cancer, making it imperative to study the mechanisms of resistance and development of therapeutic strategies that targets the tumor initiating cell population. One of the difficulties in identifying new drug targets has been that our current high throughput drug screens look for tumor shrinkage and do not incorporate the impact of compounds on the cancer stem cell population. In this review we discuss the literature on treatment resistance in breast cancer and the design of new clinical trials for test compounds which will allow us to determine both the reduction in tumor size and decrease in cancer stem cell population. In order to detect the effect of target compounds on cancer stem cells in a clinical setting, we will need to do multiple assays which include high throughput flow sorting analysis to determine the total number of CD44(+)/CD24(-/low)/Lin(-) and ALDH1 positive cells, as well as in-vitro mammosphere formation assay which is a functional assay dependent on the self renewal and anchorage independent growth properties of these cells.