Molecular classification of pheochromocytomas and paragangliomas has provided insights into their underlying biology. The largest class of these tumors is represented by transcription Cluster 2, a designation that comprises a broad group of genetic lesions loosely unified by activation of kinase signaling events and protein translation. Components of this group involve well-known members of these signaling cascades, including kinase receptor (RET), activators (RAS) or suppressors (NF1 and MAX), but also less known components, such as transmembrane protein (TMEM127), core histone (H3F3A) and other drivers. Subclassification of this cluster has proven to be challenging, possibly reflecting the high degree of redundancy and cross-talk between constituents of these various signals. We will focus on the poorly understood components of this ‘umbrella’ class of pheochromocytomas and paragangliomas to discuss biological consequences of these mutations, implications of these findings for our understanding of the origin and development of these tumors, and the challenges ahead.