Cell-free DNA (cfDNA) was discovered in human blood plasma as early as the middle of the 20th century, but it was not until a few decades ago that knowledge of human genome and epigenome in health and pathology became sufficient and methods of nucleic acid analysis became more advanced to encourage active research of the diagnostic potential of cfDNA. The use of cfDNA as a diagnostic biomarker is conventionally referred to as liquid biopsy. The following review tells a story of cfDNA discovery, summarizes contemporary views on cfDNA sources inside the body and touches upon possible prognostic and diagnostic applications of cfDNA analysis in medicine, specifically in cancer and prenatal screening, prediction of implant failure and sepsis development.