An overwhelming body of data unquestionably links the Ras-ERK pathway to cellular transformation and to the upbringing of human malignancies. Ras is the most frequent oncogene in human cancers, being detected in approximately 30% of human tumors. If to this figure, we add the cases in which activating mutations are detected, in a non-overlapping occurrence, in other component of the pathway, in particular B-Raf, the frequency nearly reaches 50%. Thus, in the past decades colossal efforts have been devoted to the development of therapeutic agents whereby aberrant Ras signals and subsequently tumor progression, could be prevented. However, a broad clinical use of these drugs, mostly classical kinase inhibitors, has been somewhat limited by peculiarities, some still unexplained, of the Ras-ERK route, by canonical resistance acquisition and by unacceptable toxicity levels. Are there alternative ways to target the Ras-ERK pathway so as to deliver more efficient while less toxic inhibitory molecules?. In this respect, for the past ten years our laboratory has been exploring two parallel venues: the spatial specificity displayed by Ras-ERK signals as a source of potentially less toxic targets and non-catalytic protein-protein interactions among components of the route as a source of more specific, less-resistance-prone objectives. In this respect, we have recently identified ERK dimerization as a promising target for anti-tumoral therapies