Currently, tissue biopsy, generally from the primary tumor, is used to determine molecular profiles at a single time point, before targeted therapy commences. Tissue biopsies carry some risks for patients, they are painful, costly, time-consuming, and most importantly, may not be a true representation of tumor heterogeneity. Tumor genomes are remarkably unstable and prone to clonal expansion under selection pressure, liquid biopsies via circulating cell-free nucleic acids offer what tissue biopsies can’t, the opportunity to take serial samples for longitudinal monitoring of tumor genomic evolution in real time. Liquid biopsy-based testing will allow clinicians to ensure treatment efficacy, monitor drug resistance, metastasis and recurrence, tailoring patients to the right treatment for the right target without delay. Tumor genome sequencing on circulating cfDNA to guide treatment decisions would be the standard-of-care of new-generation cancer management.