BC (BC) stemness contributes to aggressive primary tumor progression and increased propensity for metastasis. Additionally, BC stem-like cells (BCSCs) immensely contribute to drug resistance and relapse. Knowing the biological attributes of BCSCs is vital to employ efficacious therapies against them. In this review, we aim to cover the intrinsic characteristics of BCSCs, the autocrine signaling and paracrine activation by the available cytokines in the tumor microenvironment (TME) and opportunities for targeted therapies both intrinsic and extrinsic to BCSCs. Salient actionable molecular targets and vulnerabilities within the BCSCs and their surrounding bulk tumor and stromal cell compartments in triple-negative breast (TNBC) will be mostly discussed. Enhanced knowledge regarding the BCSCs and their microenvironment will enable us to effectively treat late stage and refractory BC.