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This review discusses the impact of gene expression profiling and sequencing discoveries on new therapeutic strategies in Non-Hodgkin Lymphomas, particularly Diffuse Large B cell Lymphoma. Alterations in oncogenes, over-active signaling pathways down-stream of the B cell receptor, and epigenetic gene mutations will be described. We will also review new targeting strategies aimed at each of these aspects of cell biology encompassing BCL2, BTK, PKCβ, PI3K/mTOR and HDAC inhibition. Specific new drugs in clinical trials and early trial results are included as well.