Since the discovery of circulating nucleic acids in plasma in 1948, many diagnostic applications have emerged. For example, diagnostic and prognostic potentials of circulating tumour-derived DNA have been demonstrated for many types of cancer. The parallel development of fetal-derived DNA detection in maternal plasma has opened up the possibility of non-invasive prenatal diagnosis and monitoring of many pregnancy-associated disorders. In this regard, non-invasive fetal rhesus blood group genotyping has already been translated to clinical practice. Other applications of circulating DNA in traumatology and transplant monitoring have also been reported. The more recent discoveries of circulating tumour-derived RNA and fetal-derived RNA have proven to be equally important as their DNA counterparts. Successful prenatal diagnosis of Down's syndrome by fetal RNA analysis has recently been reported. However, the definite origin and release mechanisms of circulating nucleic acids have remained incompletely understood, with cell death being suggested to be associated with such nucleic acid release. Pre-analytical standardisation will become increasingly relevant when comparing data from different laboratories. In conclusion, studies of circulating nucleic acids have promised exciting developments in molecular diagnostics in the years to come.