Patients with low-grade (clinically indolent) lymphomas are at risk to undergo transformation to high-grade (clinically aggressive) lymphoma, although transformation only occurs in a subset of patients. When transformation occurs it is a critical event that determines the course of disease and is associated with unfavorable patient outcomes. Accurate detection of transformation, predictive biomarkers, and identification of specific molecular pathways implicated in the pathobiology of transformation will facilitate personalized therapeutic approaches and underpin advances in clinical outcomes. In this article, we present an update of the clinical and pathologic diagnostic criteria for low-grade B-cell lymphoma transformation and discuss the molecular alterations involved in the pathogenesis of this biological phenomenon.