Next-generation sequencing techniques are powerful high-throughput methods that have enabled the comprehensive documentation of genetic lesions in numerous hematological malignancies. In recent times, the genomes of multiple different B-cell lymphoproliferative disorders including chronic lymphocytic leukemia, diffuse large B-cell lymphoma, Burkitt lymphoma, splenic marginal zone lymphoma, mantle cell lymphoma, hairy cell leukemia and Waldenström macroglobulinemia have been documented. Between them, these studies have reinforced and provided insight into the mechanisms for the dysregulation of known pathways (e.g. nuclear factor-κB [NF-κB]), uncovered the importance of new pathways for oncogenesis (e.g. mRNA processing), identified disease-defining mutations and provided meaningful new targets which are already being translated into therapeutic interventions. This review summarizes the molecular lesions that have been discovered in B-cell lymphoproliferative disorders thus far by studies utilizing high-throughput sequencing techniques and the aberrations in the numerous intracellular pathways that have been shown to be involved.