The evaluation of novel treatment regimes in ovarian cancer, ranging from cytotoxic agents and targeted therapy to surgery, demands clinically relevant mouse models to mimic human disease. These more advanced preclinical models provide a tool to obtain robust data on the mechanism of action, cytotoxicity and therapeutic efficacy of newly emerging antitumor therapies.In this chapter, we describe how to generate ovarian cancer xenograft models through injection of human tumor cell lines in immunocompromised mice. Detailed methodological descriptions are provided for both the commonly applied subcutaneous model and the more technically challenging orthotopic tumor model that involves inoculation of cancer cells in the ovarian bursa. We demonstrate how to monitor tumor growth and metastases in orthotopic ovarian models through noninvasive optical imaging and the procedures for treatment strategy, including administration of test compounds and debulking surgery. We comment on the strengths, limitations, and procedural challenges associated with each of the models.