Monitoring circulating tumor DNA enhances detection of relapse and defines molecular remission. The lead time offered by serial monitoring of ctDNA represents an opportunity for early intervention with minimal tumor burden. The clinical applications would differ when treating with curative intent (ie, aggressive lymphomas) or more extended duration of therapy (ie, indolent lymphomas). (A) Monitoring therapy for ctDNA for curative intent. The patient with no relapse (green) achieves a complete molecular remission and represents successful cure of lymphoma. The patient with late relapse (blue) initially achieves a complete molecular remission, but has ctDNA reappear before imaging, which creates a lead time for possible intervention. The patient with early relapse (red) has rising levels of ctDNA shortly after completion of therapy with a narrower lead time. The patient with primary refractory disease (brown) has persistence of minimal residual disease at the end of therapy that is undetectable by imaging. (B) Monitoring therapy with ctDNA for extended duration. Indolent lymphomas are frequently treated for extended durations with maintenance therapy designed to prolong duration of remission. Successful maintenance therapy (green) could be monitored with ctDNA and continued as long as disease remains undetectable. Patients who have the reappearance of ctDNA while receiving maintenance therapy (red) might be considered for alternative therapy before clinical effects. Patients who are not initially treated with maintenance therapy can be offered “delayed maintenance” at a time when disease is detectable by ctDNA, but not yet detectable by imaging scans.