The rapidly increasing availability of sequence information for tumor patients, combined with expanding treatment options, motivates efforts to monitor the course of disease for individual patients by analyzing patient-specific mutations in liquid biopsies, as highly specific markers of the malignancy. We discuss the suitability of established molecular methods to monitor patients with malignancies, in particular leukemias, comparing these to the recently developed super rolling circle amplification technique for highly sensitive, parallel measurements of mutant sequences using readily available instruments. The very high sensitivity for tumor-specific mutations-in combination with low cost and ready access at clinics-promises to allow routine monitoring of increasing numbers of tumor patients, in order to initiate improved treatments at the earliest timepoint possible, when necessary. A method with high-enough accuracy to enable monitoring in peripheral blood rather than bone marrow samples would present a great practical advantage, not least from the patient perspective. We describe scenarios in which sufficiently sensitive, inexpensive methods for mutational analysis can provide valuable guidance for the clinician in choosing among therapeutic options and adjusting ongoing treatment and help to promptly identify recurrences of disease in treated patients.