Extensive clinical and genetic characterization over the last 25 years has greatly improved our knowledge about the genetic basis underlying PPGLs. However, metastatic PPGL remain a diagnostic challenge, as currently there is a lack of reliable markers for stratifying high risk patients, and/or their limited predictive value continue to complicate the clinical management of PPGL patients. This is of paramount importance, and the object of intense research. Thus, application of high-throughput technologies to study PPGL has enhanced not only our understanding of tumor biology, but also has contributed to uncover potential new druggable pathways in metastatic tumours. In this regards, genome-wide DNA methylation profiling of PPGL revealed a hypermethylation phenotype, associated with mutations in Kreb’s cycle related genes. This phenotype, frequently found in metastatic cases, results in the alteration of gene expression of pathways relevant for invasion and progression. On the other hand, there is a proportion of metastatic PPGLs not associated with a hypermethylation phenotype, suggesting the existence of other still unknown mechanisms. Recently, genome-wide sequencing studies have uncovered non-mutual exclusive alterations affecting different genes, as well as chromosomal fusions in some malignant cases. All this new molecular knowledge brings us closer to solving the puzzle of the biology of aggressive PPGLs.