This study identified a new pathway involved in the pathogenesis of Burkitt's lymphoma that is amenable to therapeutic targeting. Using RNA sequencing of patient biopsy samples and Burkitt's lymphoma cell lines, together with re-analysis of published sequence data, the authors identified recurrent mutations in the transcription factor TCF3 and its negative regulator ID3. TCF3 activated the pro-survival phosphatidylinositol 3-kinase pathway in Burkitt's lymphoma cells, in part by augmenting tonic B cell receptor signalling. Inhibitors of the TCF3 pathway inhibited growth of Burkitt's lymphoma cells and tumour xenografts.