Abstract The discovery of circulating tumor DNA (ctDNA) prompted many scientists and companies to apply this new technology for cancer diagnostics. One valuable application of ctDNA is in the screening for cancer. This procedure has been coined “liquid biopsy” and unlike classical biopsy, is minimally invasive. This technology can be used to detect one, a few or several cancers, hopefully at an early, treatable stage. There is considerable debate on the ability of this technology to efficiently detect small, localized tumors since the amount of ctDNA in the circulation is miniscule, potentially leading to many false negatives. Additionally, the false positive rate is concerning, especially for low prevalence tumors. Here, we provide an update and underline important issues that need to be addressed before this technology enters the clinic. Due to substantial financial rewards of successful companies and the prospective large investment of public healthcare resources, scientists have the responsibility to thoroughly validate these technologies and make sure that these tests not only detect cancer, but they also trigger actionable interventions that improve patient survival and/or quality of life.