Basal-like breast tumors and triple negative breast tumors are high-risk breast cancers that typically carry the poorest prognoses compared with HR (Hormone Receptor)-positive tumors and HER2 (Human Epidermal growth factor Receptor 2)-amplified tumors for known therapies. These subsets of breast cancers exhibit aggressive clinical behavior, pushing margins of invasion, poor clinical outcome, and derive limited benefit from current therapy. This clinical situation is contributed and further aggravated by their less known biology, lack of obvious molecular targets, absence of favorable biomarkers, and their limited response to single-drug therapy. In 2010, Oakman et al., remarked that current therapy fails to curtail the innate aggressive behavior of TNBC (Triple Negative Breast Cancer) in the majority of patients. The poor prognosis coupled with a lack of targeted use of therapies is responsible for the high mortality in this subtype. The present review will examine the existing literature and scrutinize the difficulties that have, to date, limited the understanding of the biology of these tumor cells, and provide a rationale for the development of the concept of combining subtype-specific and pathway-specific drug targets for the therapeutic intervention of the disease.