Abstract: There is a clinical need to develop and use molecular biomarkers in minimally invasive samples to monitor disease and treatment efficacy as a complement to imaging. Circulating tumor-DNA analysis in liquid biopsies, such as blood plasma, is an emerging and promising biomarker with diagnostic and prognostic properties. However, detection of circulating tumor-DNA in clinically relevant samples requires ultrasensitive methods that enable detection of variant allele variants at low frequency. Digital sequencing offers close to error-free analysis with minimal quantification biases. We have developed a simple and flexible digital sequencing approach that is suitable to monitor patient-specific mutations with high sensitivity. Here, we will present an optimized workflow from blood sampling via digital sequencing to final clinical interpretation that is suitable for a clinical setting. We will highlight and discuss different technical and clinical considerations using circulating tumor-DNA analysis. We will demonstrate the usefulness of our approach with data from several clinical studies and tumor entities, such as melanomas, breast cancer and sarcomas. Our data suggest that circulating tumor-DNA analysis with patient-specific panels can assist in precision medicine and cancer management.