Epithelial ovarian cancer (EOC) is the fifth commonest cancer-related cause of female death in the developed world. In spite of current surgical and chemotherapeutic options the vast majority of patients have widely metastatic disease and the survival rate has not much changed over the last years. The anti- angiogenic drugs are driving the field of agents targeting the tumor microenvironment in ovarian cancer. Preclinical models that accurately reproduce the molecular and biological features of ovarian cancer patients are a valuable means of producing reliable data on personalized medicine and predicting the therapeutic response in clinical trials. In this methodological chapter we describe the orthotopic model of ovarian cancer implanted under the ovarian bursa of mice. In spite of anatomical differences between the rodent and human bursa-fallopian tube, the appropriate primary tumor microenvironment at the site of the implant allows investigation of tumor–stroma interactions (e.g., angiogenesis), and is well suited for studying the tumor dissemination and metastasis typical of this disease. This model—although fairly labor intensive—may be useful for assessing novel, more selective therapeutic interventions and for biomarker discovery, reflecting the behavior of this disease.