Pheochromocytomas and paragangliomas (PPGL) are remarkable not only because of their high heritability but also because of their genetic and phenotypic diversity. Up to fifteen different genes have now been linked to familial disease and additional somatic mutations in driver oncogenes have been found in sporadic tumours[1]. There is a strong association between the phenotypic properties of PPGL and underlying genetic drivers. Genotype to phenotype associations relate to clinicopathological features including cellular differentiation, excretory biochemical profile, metabolic activity, vascularisation and metastatic potential. Indeed many of these features are used to prioritise genetic testing, while the genotype of the tumour may dictate an appropriate surveillance strategy. Genome-wide molecular analysis of PPGL has revealed distinct “signatures” associated with underlying genotype of disease. Gene-expression profiling has identified between two and six subtypes[2-5]. Broadly, PPGL tumors cluster into two main subgroups – so-called Cluster 1 (C1) or Cluster 2 (C2). The C1 pseudo-hypoxia subgroup includes familial or sporadic tumors driven by germline or somatic mutations in VHL, EPAS1 (HIF2A), SDH subunits (SDHA, SDHB, SDHC, SDHD) and other members of the Kreb cycle pathway (FH, MDH2). The C2 subgroup represents familial or sporadic tumors with underlying RET, NF1, TMEM127, HRAS, KIF1B and MAX mutations. The SDHx and VHL tumors can be further separated by distinct gene expression patterns; and C2 tumors can also be subdivided into 3-4 minor subgroups. Gene-expression profiling clearly has an important research application for improving our understanding of the biology of disease and characterising tumours that harbour new putative gene drivers by association with tumours of known genotype. It is evident that such a classification can have clinically utility, especially as an adjunct to genetic testing. We have developed a robust gene-expression assay called “Pheo-type” that enables accurate classification of PPGL tumors[6]. Pheo-type can predict the genotype of the tumour from routine diagnostic tissue. We are now using Pheo-type classification to explore other clinical and biological associations of PPGL tumours with potential imaging and therapeutic implications.