Endometriosis is a hormone-dependent, chronic inflammatory condition affecting 5–10% of reproductive-age women, characterized by the growth of endometrial-like tissue outside the uterus, causing chronic pelvic pain and infertility. Despite its prevalence, the molecular mechanisms remain poorly understood, and current treatments focus on suppressing lesions rather than eliminating them. While generally considered benign, endometriosis increases the risk of specific ovarian cancers. Recent advances in single-cell and spatial genomics, along with organoid models, are illuminating the molecular basis of the disease. This review summarizes key genetic mutations driving endometriosis to malignancy and recent advances in understanding its molecular basis, along with novel approaches and models for improving diagnosis and treatment. Endometriosis is classified into three subtypes: superficial peritoneal endometriosis (SUP), deep infiltrating endometriosis (DIE), and ovarian endometriosis (endometriomas, OMA). SUP is the most common, while OMA is most strongly associated with ovarian cancer. The origin of endometriosis remains debated, with theories including retrograde menstruation, stem cell origin, and coelomic metaplasia. Recent studies suggest that endometriotic lesions may arise from stem cells in the endometrium or bone marrow, which can migrate and establish ectopic lesions. Genetic factors play a significant role in endometriosis, with familial clustering and twin studies indicating a heritable component. Hormonal imbalances, particularly estrogen dominance, are central to endometriosis pathogenesis. Epigenetic modifications, such as DNA methylation and histone acetylation, also contribute to hormonal imbalances and disease progression. Several cancer driver mutations, including ARID1A, PI3K/AKT/mTOR, and KRAS, are implicated in endometriosis and its progression to malignancy. These mutations are often found in epithelial cells but not in stromal cells, suggesting a role in epithelial malignancy. Endometriosis is a risk factor for ovarian cancer, with endometrioid ovarian carcinoma (ENOC) and clear cell ovarian carcinoma (CCOC) being the most common subtypes. These cancers share genetic and molecular features with endometriosis, including mutations in PTEN, PIK3CA, and other cancer driver genes. The development of 3D organoid models and single-cell omics technologies is revolutionizing the study of endometriosis, providing new insights into disease mechanisms and potential therapeutic targets. These advancements are crucial for improving diagnosis, treatment, and understanding of endometriosis and its associated cancers.Endometriosis is a hormone-dependent, chronic inflammatory condition affecting 5–10% of reproductive-age women, characterized by the growth of endometrial-like tissue outside the uterus, causing chronic pelvic pain and infertility. Despite its prevalence, the molecular mechanisms remain poorly understood, and current treatments focus on suppressing lesions rather than eliminating them. While generally considered benign, endometriosis increases the risk of specific ovarian cancers. Recent advances in single-cell and spatial genomics, along with organoid models, are illuminating the molecular basis of the disease. This review summarizes key genetic mutations driving endometriosis to malignancy and recent advances in understanding its molecular basis, along with novel approaches and models for improving diagnosis and treatment. Endometriosis is classified into three subtypes: superficial peritoneal endometriosis (SUP), deep infiltrating endometriosis (DIE), and ovarian endometriosis (endometriomas, OMA). SUP is the most common, while OMA is most strongly associated with ovarian cancer. The origin of endometriosis remains debated, with theories including retrograde menstruation, stem cell origin, and coelomic metaplasia. Recent studies suggest that endometriotic lesions may arise from stem cells in the endometrium or bone marrow, which can migrate and establish ectopic lesions. Genetic factors play a significant role in endometriosis, with familial clustering and twin studies indicating a heritable component. Hormonal imbalances, particularly estrogen dominance, are central to endometriosis pathogenesis. Epigenetic modifications, such as DNA methylation and histone acetylation, also contribute to hormonal imbalances and disease progression. Several cancer driver mutations, including ARID1A, PI3K/AKT/mTOR, and KRAS, are implicated in endometriosis and its progression to malignancy. These mutations are often found in epithelial cells but not in stromal cells, suggesting a role in epithelial malignancy. Endometriosis is a risk factor for ovarian cancer, with endometrioid ovarian carcinoma (ENOC) and clear cell ovarian carcinoma (CCOC) being the most common subtypes. These cancers share genetic and molecular features with endometriosis, including mutations in PTEN, PIK3CA, and other cancer driver genes. The development of 3D organoid models and single-cell omics technologies is revolutionizing the study of endometriosis, providing new insights into disease mechanisms and potential therapeutic targets. These advancements are crucial for improving diagnosis, treatment, and understanding of endometriosis and its associated cancers.