PURPOSE OF REVIEW: The identification of oncogenic driver mutations and activated survival pathways in selected aggressive B-cell malignancies directs the development of novel adjunctive therapies using targeted small molecule inhibitors. With a focus on diffuse large B-cell lymphoma not otherwise specified , Hodgkin lymphoma and childhood B-cell precursor acute lymphoblastic leukemia, this review will provide an up-to-date account of the current literature on the development of new molecularly targeted treatment modalities for aggressive B-cell malignancies. RECENT FINDINGS: Subclassification of B-cell malignancies depending on their particular genetic driver lesions and transcriptional and/or signaling signatures has led to the development of targeted therapeutic approaches using small molecule inhibitors to amend current combination chemotherapy. SUMMARY: Treatment outcome with current combination chemotherapy is still poor for subsets of aggressive B-cell malignancies, and demands development of targeted therapeutic approaches. Advanced gene expression profiling and genomic sequencing have revealed a more detailed landscape of recurrent alterations, allowing a better subclassification of B-cell lymphomas and leukemias. Many alterations directly or indirectly lead to activation of survival signaling pathways and expression of key oncoproteins and prosurvival molecules, including Janus kinase-signal transducer and activator of transcription (JAK-STAT), phosphatidylinositol-3 kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR), avian myelocytomatosis viral oncogene homolog (MYC) and B-cell lymphoma 2 (BCLl-2). Small molecule inhibitors targeting these proteins and pathways are currently being tested in clinical trials and preclinically to improve chemotherapeutic regimes and treatment outcomes.