The endometrium, which is the origin of endometrial cancer, already harbors cancer-associated gene mutations due to factors such as aging or menstruation, even though it is histologically normal. The complex plexus network of endometrial glands in the stratum basalis (“rhizome structure”) contributes to the accumulation of genomic alterations, leading to clonal expansion of endometrial epithelial cells with cancer-associated gene mutations. Previous studies have identified driver genes such as PTEN and TP53 in endometrial cancer and have shown that molecular subtype classifications reflect its biological characteristics more accurately than the conventional classification. Bridging the gap of genomic alterations between the endometrium and endometrial cancer is crucial for understanding the mechanisms of carcinogenesis. This chapter summarizes the genomic alterations and the associated molecular pathways in the endometrium and endometrial cancer and discusses the carcinogenesis of endometrial cancer. Further elucidation of these mechanisms is essential to enable the development of novel strategies for treating and preventing endometrial cancer.