Abstract The Eμ-myc transgenic mouse has provided a valuable model for the study of B-cell lymphoma. Making use of gene expression analysis and, in particular, expression signatures of cell signaling pathway activation, we now show that several forms of B lymphoma can be identified in the Eμ-myc mice associated with time of tumor onset. Furthermore, one form of Eμ-myc tumor with pre-B character is shown to resemble human Burkitt lymphoma, whereas others exhibit more differentiated B-cell characteristics and show similarity with human diffuse large B-cell lymphoma in the pattern of gene expression, as well as oncogenic pathway activation. Importantly, we show that signatures of oncogenic pathway activity provide further dissection of the spectrum of diffuse large B-cell lymphoma, identifying a subset of patients who have very poor prognosis and could benefit from more aggressive or novel therapeutic strategies. Taken together, these studies provide insight into the complexity of the oncogenic process and a novel strategy for dissecting the heterogeneity of B lymphoma. [Cancer Res 2008;68(20):8525–34]