The first integrative genomic analysis of a collection of 202 PPGL, carried out by the COMETE network, demonstrated that mutation status in PPGL susceptibility genes is strongly correlated with multi-omics data and revealed the crucial role of predisposing mutations as being the main drivers of PPGL. Transcriptomic studies identified two main molecular pathways, activating either the hypoxic pathway (cluster C1) or the MAPkinase/mTOR signalling (cluster C2). DNA methylation profiling uncovered a hypermethylator phenotype specific to the tumors related to a mutation in genes encoding for a protein of the tricarboxylic cycle. Succinate acts as an oncometabolite, inhibiting 2- oxoglutarate-dependent dioxygenases, such as HIF prolyl-hydroxylases and histone/DNA demethylases, explaining pseudohypoxic signature and hypermethylator phenotype. Besides, we have recently demonstrated that metastatic phenotype is associated with subsequent immortalization mechanisms. Telomerase activation or ATRX mutations are the key somatic events linked to the metastatic progression of high-risk PPGL, especially for SDHB ones. These comprehensive analysis illustrated the functional interdependence between genomic and epigenomic dysregulations as well as highlighted the interplay between genes involved in metabolism and immortalization. Furthermore, recently published novel comprehensive multiplatform analysis of 173 PPGL led by TCGA has confirmed the COMETE data and identified recurrent fusions genes by RNA sequencing. Altogether OMICs data revealed novel diagnostic and prognostic biomarkers and new therapeutic targets for patients with metastatic PPGL. New ‘omics’-based tests are going to be transferred to clinical practice to establish a precise molecular classification of primary tumor after surgery, to improve the stratification of PPGL patients at high-risk of progression, to define subgroups for targeted therapies, to establish a personalized medical management and surveillance based on circulating biomarkers. Today precision medicine is ‘En Marche’ and offers genuine hope in a favorable outcome in particular for patients with high-risk PPGL.