Diffuse large B-cell lymphoma (DLBCL), the most common subtype of non-Hodgkin lymphoma, is characterized by both clinical and molecular heterogeneity. Despite efforts to tailor therapy for individual patients, treatment remains uniform and a subset of patients have poor outcomes. The past decade has witnessed a dramatic expansion of our understanding of the genomic underpinnings of this disease, especially with the application of next-generation sequencing. In this review, the authors highlight the current genomic landscape of DLBCL and how this information provides a potential molecular framework for precision medicine-based strategies in this disease.