Multicancer detection (MCD) tests are a new generation of cancer screening tools that use a single, easily obtainable biospecimen, such as blood, to screen for multiple cancers simultaneously. These tests aim to improve early cancer detection, including cancers that currently lack effective screening methods. However, MCD tests have unknown and unquantified benefits and harms. Unlike conventional cancer screening tests, MCD tests do not specify the organ responsible for a positive result, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Two prospective studies involving over 16,000 individuals have identified cancers in organs without recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported sensitivities of MCD tests range from 27% to 95%, but they are lower for early-stage cancers. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy, including the ability to detect cancer sufficiently early for effective treatment and mortality reduction, the potential for overdiagnosis and overtreatment, and the appropriate diagnostic evaluation and follow-up for positive results. The National Cancer Institute (NCI) is funding a new research network to support studies that will rigorously assess the clinical utility of MCD technologies as cancer screening tools. Before implementing MCD tests in clinical practice, evidence from prospective clinical trials is needed to determine their effectiveness, appropriate diagnostic evaluations, and potential harms.Multicancer detection (MCD) tests are a new generation of cancer screening tools that use a single, easily obtainable biospecimen, such as blood, to screen for multiple cancers simultaneously. These tests aim to improve early cancer detection, including cancers that currently lack effective screening methods. However, MCD tests have unknown and unquantified benefits and harms. Unlike conventional cancer screening tests, MCD tests do not specify the organ responsible for a positive result, and a broad diagnostic workup may be necessary to confirm the location and type of underlying cancer. Two prospective studies involving over 16,000 individuals have identified cancers in organs without recommended screening tests, including pancreas, ovary, liver, uterus, small intestine, oropharyngeal, bone, thyroid, and hematologic malignancies, at early stages. Reported sensitivities of MCD tests range from 27% to 95%, but they are lower for early-stage cancers. False reassurance from a negative MCD result may reduce screening adherence, risking a loss in proven public health benefits from standard-of-care screening. Prospective clinical trials are needed to address uncertainties about MCD accuracy, including the ability to detect cancer sufficiently early for effective treatment and mortality reduction, the potential for overdiagnosis and overtreatment, and the appropriate diagnostic evaluation and follow-up for positive results. The National Cancer Institute (NCI) is funding a new research network to support studies that will rigorously assess the clinical utility of MCD technologies as cancer screening tools. Before implementing MCD tests in clinical practice, evidence from prospective clinical trials is needed to determine their effectiveness, appropriate diagnostic evaluations, and potential harms.