Patients with metastatic breast cancer (MBC) represent a very heterogeneous population and several factors are important for therapeutic decision: patients' characteristics including age, comorbidities, performance status, tumor biological profile, site and extension of metastatic spread, previous adjuvant therapies, and disease-free interval. New cytotoxic agents, new endocrine agents, and targeted therapies are becoming the new mainstay of adjuvant treatment. The growing understanding of the biology of breast cancer cells has led to the identification of key molecular points that represent possible targets for target-specific agents. Trastuzumab, the monoclonal antibody against the HER2 receptor, represents the standard treatment of high-risk early-stage breast cancer overexpressing HER2. With increasing use of very active drugs in the adjuvant setting, there is a greater need for effective therapy at the time of relapse. In endocrine resistant disease, a treatment-free interval > 12 months after adjuvant chemotherapy has been shown to be an important factor for drug sensitivity. If the tumor has been exposed to an anthracycline and a taxane in adjuvant setting and the treatment-free interval is > 12 months, the rechallenge with the same agents might be an option. If the treatment-free interval is < 12 months, it is preferable to use a different agent. Capecitabine, gemcitabine, and vinorelbine have demonstrated substantial activity in MBC. Novel cytotoxic agents including epothilones and vinflunine are currently in clinical development for taxane-resistant disease. Lapatinib, a new target agent that simultaneously inhibits both HER2 and epidermal growth factor receptor tyrosine kinases has been shown to be active in trastuzumab-resistant MBC. Moreover, several new agents targeting HER2 are currently under clinical development. There are no data on rechallenge with trastuzumab in patients who had received this agent as adjuvant treatment and relapsed after a long treatment-free interval, and this issue is a new area of research.