The very early intuition of Paget about the molecular feature of metastasis has come in the field of therapeutic opportunities only in the last few years with the development of targeted therapy. However, to date the diagnosis of metastases is associated in the majority of cases with the loss of any therapeutic hope. According to present knowledge, metastatic spreading is considered as part of a long process in which tumor cells gain new properties in their cellular function, including invasion and adaptive survival. This gain of function is based on the expression of new molecular markers that may be potential therapeutic targets in blocking tumor dissemination. The epidermal growth factor receptor family comprises four members (ERBB) that are frequently upregulated in advanced tumor stages and have been associated with the metastatic potential of several tumors. ERBB receptor inhibitors are very effective against specific primary tumors and their use is frequently accompanied by toxicity problems, drug resistance and molecular desensitization. However, new studies indicate that ERBB inhibitors may provide a much-needed therapeutic option mainly for patients with metastases. In order to illustrate the potential of ERBB family members as therapeutic targets in blocking metastases we summarize the new molecular evidence and the observations from clinical trials.