Detection of molecular markers of colorectal neoplasia in feces provides innovative, noninvasive means to screen for colorectal cancer and adenomas. Molecular markers, defined as a specific molecule or molecular structure, reach the gut lumen by the processes of leakage, secretion, cell exfoliation, or a combination of these processes. Exfoliated cells are the most likely to be specific for neoplasia. Fecal molecular markers will serve as the noninvasive first test in two-step screening for colorec-tal cancer, in which the second test is colonoscopy. This first step separates people into two categories: those more likely to have neoplasia and those less likely. Any new test should therefore be an improvement over the proven, but only modestly effective, guaiac-based fecal occult blood tests. The leakage marker hemoglobin can now be accurately detected by fecal immunochemical tests (FIT) for hemoglobin. These tests perform better than guaiac tests in specificity, sensitivity, and subject participation. Secreted mucins have inadequate specificity. Multitarget fecal DNA tests for exfoliated cells have not achieved their potential and have not been shown to be an improvement over FIT.