Circulating nucleic acids have been detected in plasma/serum from cancer patients with a variety of tumor types. Polymerase chain reaction techniques provide a ubiquitous and facile approach for the identification of these tumor-associated genetic alterations from a minimal amount of tissue and body fluids. Increased levels of free DNA and RNA during malignancy, as well as in various medical conditions and infectious states, offers potential clinical utility for disease screening, diagnosis, prognosis, assessing occult disease progression, identifying potential therapeutic targets and monitoring treatment response. Additionally, elevated fetal DNA and RNA circulate in maternal blood and may serve as a diagnostic aide for assessing chromosomal abnormalities, fetal sexing and monitoring complications associated with pregnancy. Issues persist regarding the characteristics, etiology and potential pathological consequences of circulating cell-free DNA and RNA. Regardless, disease surveillance using nucleic acid-based assays for the evaluation of plasma/serum and body fluids provides a non-invasive and highly practical method for assessing patients.