Apolipoprotein E (ApoE) is widely expressed in female and male reproductive tissues, playing a fundamental role in ovarian function, implantation, and pregnancy maintenance. As a primary regulator of lipid metabolism, ApoE facilitates cholesterol transport, a process essential for overall bodily homeostasis, including reproductive health. In humans, the ApoE encoding gene exists in three major allelic variants—APOE2, APOE3, and APOE4—each with distinct effects on lipid bioavailability, inflammatory responses, and maternal-fetal immune tolerance. The distinct effects of these isoforms have the potential to differentially modulate reproductive physiology, leading to differences in pregnancy outcomes and reproductive success across carriers of the different genetic variants. Understanding these genetic influences provides insights into reproductive disorders, including infertility, recurrent pregnancy loss, and pregnancy complications such as preeclampsia and fetal growth restriction. This chapter examines the role of ApoE and its genetic variants in reproductive health, focusing on their influence on lipid metabolism, steroidogenesis, inflammation, and pregnancy-related pathologies, an area of research that remains underexplored.