Effective treatment for triple-negative breast cancer (TNBC) has remained elusive since its first identification by Perou et al. in 2000. The paradox in treating TNBC lies in its initial sensitivity to standard-of-care chemotherapies including taxanes and anthracyclines yet it also develops chemoresistance to these treatments, resulting in rapid relapse and short progression-free survival. Confounding the treatment options available to TNBC patients are not only its purported lack of hormone receptor and growth factor receptor targets, but its enrichment in plastic and chemoresistant cancer stem cells (CSCs). In this thesis, I employ two strategies intended to enhance chemotherapy-induced cytotoxicity in TNBC cell lines while reducing the proportion of chemoresistant breast cancer stem-like cells (BCSCs), as defined by CD44+/CD24– and ALDH1+ phenotypes. First, I identified the expression of canonical and non-canonical progesterone receptors (PRs) in one luminal BC and three TNBC cell lines. Through targeted agonism and antagonism of these PRs in combination with Buparlisib, a pan-PI3K inhibitor, I discovered treatment combinations which enhance cytotoxicity caused by PI3K inhibition, and also found therapeutic synergy between agonist and antagonist pairings. The combinations of these drugs also elevated stress and survival signaling in multiple cell lines. Interestingly, Buparlisib treatment significantly increased the proportion of ALDH1+ BCSCs while Buparlisib combined with simultaneous PR agonism and antagonism significantly decreased BCSCs below the level of PI3K inhibition alone, to near that of the vehicle control condition. This approach highlights the advantages in manipulating progesterone receptor signaling in treating TNBC with next-generation chemotherapy and underscores the utility of reassessing the dogma of triple-negativity. Secondly, I combined Buparlisib with Olaparib, an FDA-approved PARP1 inhibitor, to assess and enhance treatment effects on cell viability and BCSC prevalence in three TNBC cell lines harboring BRCA1, PI3K, or neither mutation. Here I found cell-line specific advantages in priming cells with one inhibitor before treatment with the other and observed the development of chemoresistance after one 72-hour round of treatment. Individual and combined treatment induced stress and survival signaling, and decreased the proportion of cells in S-phase in all cell lines. Combined treatment in two cell lines resulted in increased BCSC populations and increased early apoptotic cells in all three. These findings provide insight into the deleterious effects of combined PARP and PI3K inhibition in TNBC and describe methods to improve treatment efficacy. Together, these two approaches describe advantages in combining PARP and PI3K inhibition in TNBC cell lines with and without pertinent mutations as well as in manipulating progesterone receptors in the background of PI3K inhibition. These insights into untapped opportunities in treating TNBC provide promising strategies to inform the future development of more effective therapies.