Gestational trophoblastic diseases (GTDs) include disorders such as hydatidiform moles, invasive moles, and choriocarcinoma, which result from abnormal proliferation of the trophoblast, are often associated with genetic abnormalities, and carry risks of malignant transformation, metastasis, and recurrence. Leptin (the product of the LEP gene), a key regulator of energy homeostasis, plays important roles in placental physiology—including implantation, invasion, proliferation, and survival—and is overexpressed in trophoblastic tissues from GTDs. Immunohistochemical and RT PCR studies have shown higher expression of leptin and its receptor (Ob R) in complete and partial hydatidiform moles (CHM, PHM), choriocarcinoma, and placental site trophoblastic tumors compared with normal placenta; cytoplasmic staining is stronger in cytotrophoblasts. Leptin expression is influenced by factors such as human chorionic gonadotropin (hCG) and by MAPK and cAMP/PKA signaling pathways, and epigenetic modifications (e.g., methylation of the LEP promoter) are altered in pregnancy disorders; in preeclampsia, LEP promoter hypomethylation is associated with increased leptin expression, and a similar pattern may occur in GTDs. Leptin increases trophoblast proliferation, decreases apoptosis, and regulates the cell cycle; interaction with Siglec 6 potentiates these effects. Increased plasma leptin in GTD patients suggests its potential utility as a complementary biomarker to hCG. From a therapeutic perspective, targeting leptin signaling pathways (e.g., MAPK/PI3K inhibition or use of leptin antagonists) may inhibit tumor growth. Combined molecular, cellular, and clinical studies implicate leptin and epigenetic abnormalities in GTD pathogenesis, but further research is needed to identify specific epigenetic changes and to evaluate leptin-based interventions.