Diffuse large B-cell lymphoma (DLBCL) is the most common form of lymphoma, accounting for 30-40% of newly diagnosed non-Hodgkin lymphomas. Historically, DLBCL has been thought to involve recurrent translocations of the IGH gene and the deregulation of rearranged oncogenes. Recent advances in next generation sequencing (NGS) have provided a vast and comprehensive catalogue of cancer genes involved in DLBCL pathogenesis. Whole exome sequencing (WES) of more than two hundred DLBCLs has completely redefined the genetic landscape of the disease by identifying recurrent single nucleotide variants and providing new therapeutic opportunities for the germinal center B-cell like (GCB), activated B-cell like (ABC), or primary mediastinal B-cell (PMBL) molecular subtypes. Some of these somatic mutations target genes that play a crucial role in B-cell function (BCR signaling, NF-κB pathway, NOTCH signaling, Toll-like receptor signaling, and the PI3K pathway), immunity, cell cycle/apoptosis, or chromatin modification. In this review, we present an overview of the mutations recently discovered by NGS in DLBCL and discuss their biological relevance and possible impacts on clinical management.