The analysis of circulating cell-free nucleic acids is being introduced in several medical fields. In obstetrics, noninvasive prenatal aneuploidy screening for trisomy 21 is well established and widely implemented with high sensitivity and specificity [1]. In transplantation medicine, the amount of circulating donor-derived cell-free DNA in the recipient is being explored as a surrogate marker for cellular damage in the donated organ. The analysis of tumor-derived cell free DNA and RNA is emerging as an alternative to or complementary assay for molecular genetic analyses in tumor tissue biopsies. Commonly referred to as liquid biopsies, the most widely adopted source is blood although other easily accessible body fluids, such as saliva, pleural effusions, urine, or cerebrospinal fluid (CSF), can also serve as sources for liquid biopsies. Moss et al. used cell type-specific methylation to track cell origin, identifying 55% of cell-free DNA in healthy individuals as originating from white blood cells, with contributions from erythrocyte progenitors (30%), vascular endothelial cells (10%), and hepatocytes (1%). Cell free nucleic acids are thought to originate from apoptotic or necrotic tissue under physiological and pathological circumstances, but exact biological origins and roles are still under investigation. The fraction of cell-free DNA originating from the tumor is sometimes referred to as circulating or cell-free tumor DNA both abbreviated as ctDNA, which we will use throughout this review. Circulating tumor cells and extracellular vesicles (30– 100 nm diameter) originating from tumor cells known as exosomes are other biological sources for DNA, RNA, and proteins in liquid biopsies. This review is limited to the analysis of ctDNA, the most widely adopted fraction. Siravegna and Wan have comprehensively reviewed how other types of liquid biopsies can be exploited to guide patient care, while Merker et al.  We refer the reader to these reviews for more information on those topics.