The identification of mechanisms that regulate proliferation and survival of tumor cells is leading to the development of novel therapeutic approaches.To date, several agents specific for molecular targets amplified or over expressed in cancer cells have been generated.Owing to their high selectivity, these drugs generally have fewer side effects as compared with most conventional chemotherapeutic agents, and can be combined with conventional therapies to improve the response to treatment without a major increase in side effects.It might be argued that target-based agents are active when their targets play a key role in tumor growth, such as ErbB-2 in breast tumors that over express this receptor.However, it must be emphasized that the majority of ErbB-2 positive patients have mechanisms of resistance to trastuzumab at diagnosis.In fact, only 30% of patients with advanced ErbB-2-positive breast cancer respond to trastuzumab as first-line therapy, and the response rate drops to 15% in pretreated patients.Furthermore, almost all patients will become resistant to the drug during the course of the treatment.Therefore, the main question that we need to address in order to improve this therapeutic approach is why tumors do not respond to target-based agents.