The population of patients diagnosed with colorectal cancer (CRC) is increasingly younger. The median age for the diagnosis of CRC shifted from 72 years in the early 2000s to 66 years in 2020.1 This is because CRC incidence is increasing among adults younger than 50 years and decreasing in older age groups.2 Lower gastrointestinal screening endoscopy has the potential to reduce cancer incidence by identifying a treatable premalignant condition (ie, adenomatous or serrated polyps) and to reduce cancer mortality by enabling diagnosis of malignant disease at an earlier stage. In the past 4 years, the American Cancer Society3 and the US Preventive Services Task Force4 recommended lowering the age for screening to 45 years for those at average risk of CRC. This qualified recommendation was made on the basis of microsimulation models of CRC screening in a hypothetical cohort of 40-year-old eligible patients.5,6 Qualified means that although clear evidence of benefit exists, so does uncertainty about whether the benefits outweigh the harms of screening endoscopy for younger individuals at average risk of CRC. In this issue of JAMA Oncology, Ma et al7 addressed the lack of empirical data demonstrating the utility of earlier screening through an analysis of the Nurses’ Health Study II,8 with data collected between 1991 and 2017. Among 111 801 women with more than 2 decades of follow-up, the authors examined associations between endoscopy initiation at different ages and risk of incident CRC. The authors found that compared with no endoscopy, initiation of endoscopy before 50 years of age was associated with a reduced risk of CRC; they also found a greater reduction in the absolute risk of CRC through 60 years of age associated with endoscopy initiation before 50 years of age compared with initiation at 50 years of age or later. Previous large observational studies, including an emulation of a clinical trial of CRC screening,9 have sought to quantify the real-world benefit of endoscopy in terms of CRC incidence in the population of adults aged 50 years or older. We discuss how well observational studies can address questions regarding CRC prevention for which we are ultimately seeking answers. Does early CRC screening save lives? Can screening strategies for adults younger than 50 years at average risk for CRC be personalized?