The Ras gene family has been implicated in the development of many human epithelial cancers. Mutations in K-ras or its downstream mediator BRAF have been detected in about two thirds of low-grade serous carcinomas and borderline serous tumors; mutations in K-ras are also often present in benign and invasive mucinous ovarian cancers. Although the oncogenic allele H-ras(V12) is present in only approximately 6% of ovarian cancers, physiologically activated H-ras protein is commonly detected in human ovarian cancer, presumably because of an increase in upstream signals from tyrosine kinase growth factor receptors such as Her-2/neu, despite the lack of a Ras mutation. The mechanisms by which ras oncogenes transform human epithelial cells are not clear. The methods described here are what we use to culture human ovarian surface epithelial cells, to immortalize those cells, and to transform the immortalized cells with oncogenic H-ras or K-ras. These Ras-transformed human ovarian surface epithelial cells form tumors in nude mice and recapitulate many features of human ovarian cancer, thus providing an excellent model system for studying the initiation and progression of human ovarian cancer.