Triple negative breast cancer (TNBC) is the most lethal form of breast cancer. Treatment options for advanced disease are limited, with a median survival from the time of developing metastases rarely exceeding 1 year. TNBC is heterogeneous, and harbours several molecular alterations. Unfortunately, up to now, clinical trials combining targeted agents and chemotherapy have failed to show substantial survival improvement; therefore, chemotherapy remains the backbone of treatment. No major advances have been made in the field of cytotoxic treatments, and hopefully ongoing trials will contribute to a more precise definition of the role of platinum salts in sporadic and BRCA-mutated TNBC. Moreover, recent gene expression data suggest that TNBC can be further segmented into smaller subgroups, characterized by different activated pathways, which may therefore warrant different targeted treatments. The lack of efficacy that has been observed for the majority of targeted agents in TNBC so far may derive from the inclusion of unselected TNBC patient populations, not enriched for patients presenting an alteration in the target. Therefore, one of the major challenges in the future is to integrate biological data into clinical trials to obtain the highest efficacy from promising targeted treatments such as anti-angiogenetic agents, poly (ADP-ribose) polymerase-1 (PARP), epidermal growth factor receptor, fibroblast growth factor receptor, androgen receptor and phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibitors.