Major progress in the understanding of diffuse large B-cell lymphoma (DLBCL) biology has been made in the last decade. Many specific compounds have now entered early phase clinical trials. However, further efforts are needed to find an accurate, fast, reproducible, and affordable technique to translate DLBCL subtype determination by gene expression profiles into clinical application. This article discusses the advantages and drawbacks of the currently available techniques of DLBCL subtype determination as well as important prognostic implications related to the cell of origin. Furthermore, the article provides a schematic description of how molecularly defined DLBCL subtypes could guide tailored therapy.