Several important lessons have been learnt from our experiences in screening for various cancers. Screening programmes for cervical and colorectal cancers have had the greatest success, probably because these cancers are relatively homogenous, slow-growing, and have identifiable precursors that can be detected and removed; however, identifying the true obligate precursors of invasive disease remains a challenge. With regard to screening for breast cancer and for prostate cancer, which focus on early detection of invasive cancer, preferential detection of slower-growing, localized cancers has occurred, which has led to concerns about overdiagnosis and overtreatment; programmes for early detection of invasive lung cancers are emerging, and have faced similar challenges. A crucial consideration in screening for breast, prostate, and lung cancers is their remarkable phenotypic heterogeneity, ranging from indolent to highly aggressive. Efforts have been made to address the limitations of cancer-screening programmes, providing an opportunity for cross-disciplinary learning and further advancement of the science. Current innovations are aimed at identifying the individuals who are most likely to benefit from screening, increasing the yield of consequential cancers on screening and biopsy, and using molecular tests to improve our understanding of disease biology and to tailor treatment. We discuss each of these concepts and outline a dynamic framework for continuous improvements in the field of cancer screening.