Cell-free circulating tumor DNA (ctDNA) and circulating tumor cells (CTCs) can be found in the bloodstream of individuals with cancer and are increasingly being explored as biomarkers in various aspects of cancer management. The application of next-generation sequencing (NGS) technologies to ctDNA and CTC analysis are providing new opportunities to characterize the cancer genome from a simple blood test and can facilitate the ease with which tumor-specific genomic changes can be followed over time. The serial analysis of ctDNA and CTCs has enormous potential to provide insights into intratumor heterogeneity and clonal evolution during disease progression, and may ultimately allow noninvasive molecular disease monitoring to guide therapeutic decisions and improve patient outcomes.