Next generation sequencing (NGS) technology has led to a burst of disease-relevant molecular information in a variety of lymphoid tumors, including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, follicular lymphoma, mantle cell lymphoma, Burkitt lymphoma, Waldenström macroglobulinemia, hairy cell leukemia, and splenic marginal zone lymphoma. Beside disclosing comprehensive catalogs of somatic mutations and new insights into the genes that contribute to cellular transformation, NGS has also provided molecular clues useful for addressing a number of unmet clinical needs in the field of B-cell tumor management, including biomarkers for disease diagnosis and classification improvement (i.e. mutations of BRAF, MYD88 and NOTCH2), and new targets to be translated into therapeutic interventions (i.e. BCR, TLR, NOTCH, NF-κB and MAPK signaling pathways). This review summarizes the molecular lesions of signaling pathways that have been discovered in B-cell lymphoproliferative disorders by NGS studies.