Serial monitoring with circulating tumor DNA to guide precision medicine. Lymphomas are composed of multiple tumor clones and subclones that serially evolve over time, especially under the selective pressure of therapy. Liquid biopsies of ctDNA detect molecular features of resistant disease at the molecular level and can noninvasively genotype ctDNA throughout the disease course. Serial monitoring of ctDNA may be a powerful tool to address temporal heterogeneity of tumors, to detect clonal evolution, and to study mechanisms of treatment resistance. The timing and nature the dominant relapsing clone may guide precision treatment at relapse. As examples, patients who relapse with a myc rearrangement (green) might be offered targeted therapy with a BET inhibitor, whereas patients who relapse with a TP53 mutation (magenta) could be offered an MDM2 inhibitor.