An increasing number of neoplasms are associated with variably specific genetic abnormalities. This is best exemplified by hematological malignancies, in which there is a growing list of entities that are defined by their genetic lesion(s); this is not (yet) the case in mature B-cell lymphomas. However, enhanced insights into the pathogenesis of this large and diverse group of lymphomas have emerged with the ongoing unraveling of a plethora of fascinating genetic abnormalities. The purpose of this review is to synthesize well-recognized data and nascent discoveries in our understanding of the genetic basis of a spectrum of mature B-cell lymphomas, and how this may be applied to contemporary clinical practice. Despite the explosion of new and exciting knowledge in this arena, with the potential for enhanced diagnostic and prognostic strategies, it is essential to remain cognizant of the limitations (and complexity) of genetic investigations, so that assays can be developed and used both judiciously and rationally.