To evaluate the efficacy of cancer screening, investigators have turned increasingly to the case-control approach as an efficient alternative design to the randomized controlled trial. Overlooked in the design and implementation of screening case-control studies, however, have been important clinical distinctions that are crucial for decisions in patient management and health policy. These distinctions involve the classification of baseline risk factors and prognostic co-morbidity, the enumeration and definition of the intervention, and the choice and timing of the outcome. When investigators neglect the distinctive characteristics of patients and their diseases, screening case-control studies may have reduced validity and impaired utility. To strengthen the validity of these studies, investigators can analyze co-morbidity suitably, report a "clinical" confidence interval as the estimate of screening efficacy, carefully evaluate the attribution of death, and allow sufficient follow-up time for the death of patients diagnosed with cancer. Moreover, to strengthen the generalizability of screening case-control studies, investigators can stratify their findings for pertinent baseline risk factors and can expand the screening definition. If implemented, these guidelines may enhance the capacity of case-control studies to provide clinicians and policy-makers with critically needed information on the efficacy of cancer screening.