Targeted therapies affecting specific molecular target, expressed preferentially by neoplastic cells, block cancer growth. Current targets are represented by cell-surface trans-membrane proteins, intracellular proteins, and by growth factors. Today a targeted therapy exists for most commonly diagnosed types of human cancer often combined with chemotherapy or sometimes as monotherapy option. The epidermal growth factor receptors (EGFR) and vascular endothelial growth factors (VEGF) are known as the two main control key intracellular pathways, governing fundamental processes in cancer cells. The concept of using anti-EGFR and anti-VEGF strategies, as cancer treatment, has been recently developed and exploited extensively. We review targeted drugs currently available for routine treatment of lung, breast, colorectal and renal cell cancers, summarizing the history of identification and molecular characterization of targets or signaling pathways responsible for abnormal cell growth. We also focus on new targeted strategies, still under investigation, able to affect simultaneously tightly interconnected biological pathways or directed against new molecular targets.