Clinical trials of inhibitors against individual receptor tyrosine kinases (RTKs) in glioblastoma have not yielded promising results. By analysing DNA copy number data sets, Szerlip et al. determined that 36 of 583 glioblastoma cases had amplification of two or more RTKs in separate cell populations within a tumour. Fluorescence in situ hybridization analysis of epidermal growth factor receptor (EGFR) and platelet-derived growth factor receptor-α (PDGFRA), the most commonly amplified RTKs, showed distinct cells expressing each RTK. Furthermore, DNA sequencing revealed a common clonal origin of these cells. Cell lines derived from these tumours contained cells with either EGFR or PDGFRA amplification. Inhibition of both RTKs was required to block PI3K signalling in these cells, and this may be required to achieve therapeutic benefit in patients with co-amplified RTKs.