Breast cancer (BC) is the most diagnosed cancer worldwide and one of the main causes of cancer deaths. BC is a heterogeneous disease composed of different BC intrinsic subtypes such as triple-negative BC (TNBC), which is one of the most aggressive subtypes and which lacks a targeted therapy. Recent comprehensive analyses across cell types and cancer types have outlined a vast network of protein–protein associations between transcription factors (TFs). Not surprisingly, protein–protein networks central to oncogenesis and disease progression are highly altered during TNBC pathogenesis and are responsible for the activation of oncogenic programs, such as uncontrollable proliferation, epithelial-to-mesenchymal transition (EMT) and stemness. From the therapeutic viewpoint, inhibiting the interactions between TFs represents a very significant challenge, as the contact surfaces of TFs are relatively large and featureless. However, promising tools have emerged to offer a solution to the targeting problem. At the clinical level, some TF possess diagnostic and prognostic value in TNBC. In this review, we outline the recent advances in TFs relevant to TNBC growth and progression. Moreover, we highlight different targeting approaches to inhibit these TFs. Furthermore, the validity of such TFs as clinical biomarkers has been explored. Finally, we discuss how research is likely to evolve in the field.