Diffuse large B-cell lymphoma (DLBCL) is a clinically and pathologically heterogeneous entity. Multiple molecular methods have been used to further understand and define this heterogeneity. Gene profiling has identified “cell-of-origin” molecular subtypes of DLBCL based on expression patterns similar to normal B-cells. These molecular subtypes are germinal center B-cell–like DLBCL and activated B-cell–like DLBCL and have been correlated with prognosis. These subtypes have also been associated with additional molecular alterations and preferential activation of specific oncogenic pathways. Other array-based molecular techniques such as microRNA, comparative genomic hybridization, and single nucleotide polymorphism arrays have also been applied to identify recurrent microRNA and gene copy number alterations. Most recently, next-generation whole-exome and whole-genome sequencing have provided further insight into the spectrum of genetic alterations in DLBCL. The biologic significance of these discoveries continues to be elucidated; however, emerging data are already informing treatment strategies that may target altered B-cell receptor signaling pathways and dysregulated epigenetic pathways. It will be important for pathologists to be familiar with the advances in our understanding of the molecular pathogenesis of DLBCL because they will certainly impact routine diagnosis, classification, and therapeutic decisions.