The present paper is a critical review about the recent development of new agents that have revolutioned the therapeutical approach of solid tumours with a particular focus on colorectal cancer. Until a few years ago, chemotherapy has been considered the only medical treatment for advanced disease. At the moment, new drugs blocking some cell functions, such as monoclonal antibodies or tyrosin kinase inhibitors are available for many oncologists, but their efficacy should be debated for several reasons. Despite having a strong biological and preclinical rationale, the clinical results of these agents are not comparable to the results obtained by imatinib in gastrointestinal stromal tumour or in chronic myeloid leukaemia even though superior to chemotherapy alone. Moreover, the efficacy does not show any correlation with the molecular expressions of the tumours. In this review, we considered different hypotheses in order to explain these results.