Response assessment in lymphoma relies on imaging scans that do not capture biologic processes at the molecular level. Monitoring circulating tumor DNA (ctDNA) with next-generation sequencing-based assays can detect recurrent disease prior to scans and "liquid biopsies" for somatic mutations address tumor heterogeneity, clonal evolution, and mechanisms of resistance to guide precision treatment. Preanalytic collection and processing procedures should be validated and standardized. We describe emerging applications of ctDNA monitoring including real-time analysis of tumor dynamics, preclinical disease detection, and precision-directed treatment paradigms.