AbstractAdvances in cancer screening and early detection methodologies may lead to the detection of precancerous lesions or early-stage cancer. The development of blood-based multi-cancer early detection (MCED) tests may aid in this challenge. Furthermore, MCED tests have the potential to address early detection gaps for cancers with and without screening modalities and lessen cancer disparities, but many unknowns remain. In this issue, Clarke and colleagues describe stage- and cancer-specific incidence and survival, derived from Surveillance, Epidemiology and End Results Program Data, stratified by race/ethnicity and sex. The investigators discuss the potential to identify earlier-stage cancers (stage shift) that could improve overall patient outcomes. In a simulation model, the authors found fewer cancer-related deaths when cancers were down-staged at the time of diagnosis. In this commentary, we discuss some unanswered questions in using MCED tests for screening, as well as what stage shifting may actually mean for patient outcomes.See related article by Clarke et al., p. 521