The ovulatory surge of LH triggers extensive structural, cellular, and molecular changes in the periovulatory follicle, leading to ovulation and corpus luteum (CL) formation. In recent years, it has become apparent that hypoxia plays an important complementary role in CL formation. The hypoxic microenvironment in this fast-growing tissue is a major contributor to its ability to survive by inducing an intricate vascular network. The intense angiogenic process during CL formation results in an extremely high rate of blood flow in the mature gland, which facilitates nutrient intake and hormonal (progesterone) discharge. Vascular endothelial growth Factor A (VEGFA), fibroblast growth Factor 2 (FGF2), and prostaglandin endoperoxide 2 (PGE2) are implicated in luteal angiogenesis. The neovascularization is accompanied by extensive extracellular matrix (ECM) remodeling. Cellular responses to hypoxia are mediated by hypoxia-inducible factor 1A (HIF1), an oxygen-regulated transcriptional activator. Two prominent HIF1-dependent luteal genes are discussed: VEGFA and endothelin-2; these factors affect ovulation, angiogenesis, and CL formation. MicroRNA-210 (miR-210), known as hypoxiamiR, is a critical element of HIF1A-dependent responses in granulosa-lutein cells. These HIF1A/miR-210pathways are similarly used by the two main signals driving CL formation, namely, hypoxia and LH.