Cancer development, like most other human diseases, is the consequence of functional cellular alterations that drive to deregulation of tissue homeostasis. These modifications translate into stronger survival abilities and profound re-adjustments of the subtle balance between proliferative rates and regulated cell death programs. Moreover, further alterations in selected cell sub-clones allow specific cells not only to invade into the local surrounding tissue, but also to enter the systemic circulation - via lymphatic or blood vessels - and to establish new cancer colonies in a host organ. Because of the central role that the protein network plays in cellular function and in maintenance of normal cellular homeostasis, proteomics has become an intense focus of study in oncology today. In this context, technological approaches such as Reverse Phase Protein Microarray that utilize small input samples such as fine needle aspirants or tiny core biopsy samples, routinely used for analysis of metastatic lesions, could have a dramatic impact at the bedside as the gatekeeper for therapeutic selection for each patient. Several studies revealed discrepancies between pathway activation in the primary tumor and in the hepatic metastases, indicating an influence not only of the primary tumor but also of the host microenvironment in the development of metastases. These findings highlight the importance of metastatic lesion profile analysis and suggest its potential in selecting patients for therapy. The use of data derived not only from the primary tumor but also from tumors in secondary sites that ultimately drive the course of the disease is fundamental for clinical decision to increase therapeutic efficacy as well as in the development of new, more specific, compounds for the treatment of metastatic cancer.