Emerging methods to detect tumor-derived DNA in the blood plasma of patients with lymphomas—so-called “circulating tumor DNA” (ctDNA)—have the potential to change the way in which lymphoma is diagnosed and managed in the clinic. The possible applications for ctDNA are numerous, including mutation genotyping, response monitoring, and detection of minimal residual disease during a time of radiographic remission. This article discusses the methodology for detecting ctDNA in aggressive B-cell lymphomas, including digital polymerase chain reaction, targeted sequencing of immunoglobulin receptors, and targeted next-generation sequencing. The advantages of each of these methods are also compared, with a focus on promising clinical applications. These include identification of molecular subtypes (eg, cell-of-origin and double-hit lymphomas) from pretreatment plasma, molecular response prediction after an initial course of therapy, and early detection of relapsing disease prior to clinical relapse. Finally, this article discusses the challenges in implementing ctDNA assays in the clinic today, including possible solutions to these challenges.