Breast cancer is the most commonly diagnosed and the second highest cause of cancer-related mortality. Although major breakthroughs have emerged during the past decades concerning the characterization of major malignant tumors hallmarks, little is known about the molecular process that sustains the most deadly feature of cancer: metastasis to distant organs. In fact, this colonization of tumor cells to secondary sites is not random but rather orientated, and depends on several signalling events that are not fully elucidated yet. Understanding the precise molecular and cellular mechanisms accountable for the specific invasion of tissues by breast cancer cells is likely to be important for developing new therapeutic strategies to effectively prevent metastasis in patients diagnosed with early cancer lesions. Here, we briefly describe a multidisciplinary approach based on the molecular profiling of breast cancer metastases, the elaboration of prognostic gene signatures, the clinical validation and the experimental confirmation using cell and animal models to better address breast cancer metastasis. This methodology can be considered as a useful workflow to identify and validate the genes that trigger and support organ tropism of breast cancer cells during metastasis.