The progressive diffusion of genomic profiling tests based on next-generation sequencing (NGS), the development of new mutation-driven drugs, and the "agnostic approval" processes of FDA and EMA represent a considerable phenomenon in the development of oncology and Precision Medicine. These have started the mutational oncology model that supports and integrates the traditional histological one. This new model, although still preliminary, is deeply different from the histological method. Its high complex management affects several variables concerning scientific, organizational and re-organizational, ethical and privacy aspects. It inevitably requires the activation of inter-disciplinary groups (Molecular Tumor Board), in order to govern clinical and decisional processes for appropriateness. New oncological target therapies can be an additional value in the treatment of rare tumors and of patients without therapeutic alternatives. Nevertheless, there is a documented risk that an uncontrolled use of NGS tests and of mutation-driven drugs can compromise there appropriateness compared to standard and consolidated medicines, and determine the economic unsustainability. In order to avoid these problems, a central governance (AIFA and Regions) of criteria for using tests and selection of target therapies is essential.