HIF is stimulated by both hypoxia and O2-independent oncogenic, metabolic, and therapeutic factors. HIF drives angiogenesis by inducing secretion of proangiogenic growth factors by tumor cells and stromal cells, such as adipocytes and fibroblasts. The newly formed vasculature is disorganized and leaky, which facilitates tumor cell invasion and metastasis, impairs drug delivery, and further aggravates hypoxia in the tumor and the microenvironment. Angiogenic growth factors also contribute to an immunosuppressive tumor microenvironment, particularly by increasing recruitment of immunosuppressive cells. Compounds targeting angiogenic key players are listed in pink text. The key indicates their furthest stage of development in the breast cancer setting and evaluation in clinical trial(s) as monotherapy or as combination therapy. ANGPT(L), angiopoietin(-like) protein; BRCA, breast cancer gene; ER, estrogen receptor; FGFR, fibroblast growth factor receptor; HER, human epidermal growth factor receptor; MET, hepatocyte growth factor receptor; PARP, poly (ADP-ribose) polymerase; PTEN, phosphatase and tensin homolog; RET, rearranged during transfection; TAM, tumor-associated macrophage.