<p>Globally, colorectal cancer (CRC) is the second leading cause of cancer death and the third most common incident cancer. CRC begins as adenomatous or serrated polyps, and in particular as advanced precursor lesions (APLs), which have the potential to progress into invasive cancers. Screening for CRC facilitates early detection and can identify cancers more amenable to cure, and can also detect and remove precursor lesions, thus also preventing CRC. Colonoscopy is the mainstay of screening in the USA and has the distinct advantage of enabling both detection and removal of precursors lesions. However, colonoscopy is burdensome, expensive and invasive, and often has negative findings. Non-invasive tests, such as testing stool samples for biomarkers of risk, have the potential to identify individuals who are more likely to benefit from colonoscopy. From a public health perspective, improving compliance with screening remains a priority. Technological innovations, including the emergence of new markers to improve stool testing and the development of blood tests that examine cell-free DNA have the potential to improve screening uptake and effectiveness. The trade-off between uptake of screening testing, detection of cancer and important precursor lesions such as APLs, and costs make for a complex calculus. In this Review, we describe the current state of CRC screening and evaluate the risks and benefits of new developments in screening.</p>