Notch is a cell-signaling pathway that is highly conserved in all metazoans and is responsible for cell differentiation and cross-talk communication with other signaling pathways such as WNT and Hh. In most cancers, the Notch signaling pathway is altered, causing atypical activity of vital processes such as cell cycle, differentiation and apoptosis, leading the cell to a carcinogenic state. Currently, the Notch signaling pathway has taken a special interest to design strategies in order to regulate the activity of this pathway since it is known that in the cancer molecular micro-environment the Notch pathway is over-expressed or presents an aberrant function, which, in consequence, corrupts the cross-talk communication with WNT and Hh pathways. Most of the existing strategies are focused on the systematic and whole inhibition of Notch pathway at the membrane level by the use of γ-secretases inhibitors. There are few strategies that act at the nuclear level inhibiting the activity of the transcriptional activation complex composed by the Notch intracellular domain, the transcriptional factor CSL and the Mastermind co-activator. In this review, by the fact that there are not any strategy focused to revert the over expression effect caused by the Notch pathway constitutive activity, we propose that the efforts to develop new strategies against cancer should be focused to understand the complexity of the cross-talk communication between Notch, WNT and Hh pathways to neutralize the gene aberrant activity characteristic of cancer cells which are responsible for those corrupted cross-talk communication.