Our clinical development strategies for targeted therapies are based on the biological understanding of the targeted pathway, its relevance for tumorigenesis, in vitro and in vivo data and early clinical signs in FIM trials.Preclinical Phase 2 trials are now used assuming improved predictability.This is more straightforward in case of selective specific inhibitors but less evident with multikinase inhibitors.Pathway interrelations are now recognized contributing to primary or acquired resistance.The growing understanding of these inter-pathway networks has trigger more rationale novel-novel combinations.