Dissemination of breast cancer cells (BCCs) to distant sites (metastasis) is the ultimate cause of mortality in patients with breast cancer. Hypoxia (low O₂) is a microenvironmental hallmark of most solid cancers arising as a mismatch between cellular O₂ consumption and supply. Hypoxic selection of BCCs triggers molecular and cellular adaptations dependent upon hypoxia-inducible factors (HIFs), a family of evolutionarily conserved transcriptional activators that coordinate the expression of numerous genes controlling each step of the metastatic process. In this review, we summarize current advances in the understanding of HIF-driven molecular mechanisms that promote BCC metastatic dissemination and patient mortality. In addition, we discuss the clinical and therapeutic implications of HIF targeting in breast cancers.