The gene encoding the MEF2B transcription factor is mutated in germinal center (GC)-derived B cell lymphomas, but its role in GC development and lymphomagenesis is unknown. We demonstrate that Mef2b deletion reduces GC formation in mice and identify MEF2B transcriptional targets in GC, with roles in cell proliferation, apoptosis, GC confinement, and differentiation. The most common lymphoma-associated MEF2B mutant (MEF2BD83V) is hypomorphic, yet escapes binding and negative regulation by components of the HUCA complex and class IIa HDACs. Mef2bD83V expression in mice leads to GC enlargement and lymphoma development, a phenotype that becomes fully penetrant in combination with BCL2 de-regulation, an event associated with human MEF2B mutations. These results identify MEF2B as a critical GC regulator and a driver oncogene in lymphomagenesis.Keywords: B cell; MEF2B; germinal center; lymphoma; mouse model.