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Breast cancer remains one of the most prevalent and deadly malignancies in women. Metastasis remains an unmet clinical need specially in some subtypes such as triple negative breast cancer. Among non-metastatic patients, more than 40 % fail to achieve a complete pathological response during the course of treatment, facing high rates of local failure post-resection and distant metastases. Recent studies suggest an association between the presence of circulating tumor cells (CTCs) and the aggressiveness of the disease. Herein, we describe an orthotopic syngeneic mouse model in which tumor cells are directly inoculated into the exposed mammary gland. This model allows mechanistic studies on tumor progression and the evaluation of novel therapeutic strategies. Furthermore, the inclusion of surgical resection of established tumor closely mimics current clinical approaches in breast cancer treatment and enables the investigation of mechanisms underlying tumor relapse and metastasis. This chapter outlines the complete protocol, including all necessary steps and materials, for establishing a metastatic breast cancer model in mice. The model is based on CTCs that persist in the bloodstream and subsequently colonize distant organs (primarily the lungs) following surgical resection of the primary tumor.