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The Papanicolaou smear, a routine screening test for cancer of the uterine cervix, was reported in 1928, and its efficacy was proved by 1941. Since then, it has been used worldwide as a clinical tool for the early detection of cancer. Cancer of the cervix follows a predictable sequence. Precancerous changes, not visible to the naked eye, are detected readily in cells sampled by the Papanicolaou smear. The evolution from the precancerous stage to cancer is slow, and routine annual screening makes this a curable cancer and totally preventable disease. This is the story of an ambitious and brilliant man, George Papanicolaou, and his devoted wife, Andromache Mavroyenous, whose discovery of the screening test is now recognized as the most significant advance in the control of cancer in the 20th century.