Cancer cells hyperactivate signalling molecules, including EGFR, Akt and the angiogenic factor VEGF to escape apoptosis, thus contributing also to resistance to treatment. While single signalling inhibitors have produced limited advantages in clinical trials, their combination with conventional treatments is more effective; however, the rate of responses is generally around 20%. A major limitation is represented by the activation of escape pathways, due to an intensive cross-talk and redundancy of signals in the transduction network. A novel and more rational approach is the combination of multiple signalling inhibitors, according to the molecular context of disease, in combination with selected conventional treatments.