Liquid biopsies allow for easy sampling of a cancer’s genome by a simple blood draw. This not only enables access to crucial molecular information in patients that have difficult-to-biopsy lesions, but it also provides an opportunity to gain insight into a cancer’s heterogeneity across multiple lesions (spatial heterogeneity). Furthermore, it enables us to capture the clonal evolution of a cancer over time (temporal heterogeneity). To this end, we have developed a novel liquid biopsy-based targeted sequencing platform, utilizing unique molecular identifiers and in silico background suppression to achieve superior sensitivity and specificity. Based on this, we have initiated a large-scale genomic profiling study of Hodgkin lymphoma and have investigated persistence of somatic mutations in plasma as a marker for minimal residual disease (MRD). Since then, we are integrating our findings into the development of dynamic risk profiling strategies with the ultimate goal of integration into clinical trials. Beyond Hodgkin lymphoma, we have a particular interest in aggressive B-cell malignancies, lymphomas arising in immune-privileged sites and clonal evolution during the course of novel therapeutic strategies. With many hundred patients analyzed, our robust experience in liquid biopsies has led to several collaborations including lung cancer, esophageal cancer, hepatocellular carcinoma, and sarcoma.