This review summarizes methodologic theories for the design of cancer screening case-control studies and examines the methods applied in studies published in English from 1980 through 1996. In addition to summarizing state-of-the-art methodologic approaches, we identify areas where obvious gaps exist between theory and practice, and we recommend potential areas where theory and methodology may need further development. In particular, we focus on three major areas: 1) the selection of case and control subjects, 2) the definition of exposure (i.e., exposure to the screening test), and 3) bias. Each area is considered carefully by summarizing current theory, reviewing cancer screening applications, and linking recommended methodologic approaches to those used in practice to identify areas where inconsistencies exist. In general, we found methodologic theory and practice in this field of research to be consistent. However, discrepancies were identified in the area of exposure definition, including the use of screening frequency and the use of a detectable, curable preclinical phase for case subjects as the exposure measures. Even when recommended methods were followed, a number of difficulties arose in practice. Specific concerns included the ability to carry out the following: identifying all case subjects within a source population, defining eligibility criteria to ensure that case and control subjects had equal access to screening during the exposure period, distinguishing between symptomatic and diagnostic tests, and controlling for self-selection bias. Careful scrutiny is warranted in all aspects of the design of cancer screening case-control studies, and caution is advised in the interpretation of study results.