In this paper we discuss approaches to two distinct problems in using large computerized databases to conduct population-based case-control studies. The first topic, concerning case ascertainment, is a methodologic problem, and the second, concerning confounding by indication, is an analytic problem. The first involves attempting to ascertain all incident cases of coronary disease among enrollees of Group Health Cooperative of Puget Sound (GHC), a large health-maintenance organization. Methodologic studies reported here have helped us improve the efficiency of using the large computerized databases for case ascertainment at GHC. The second problem involves the issue of confounding by drug indication. Drugs such as beta-blockers have multiple indications, including the treatment of both high blood pressure and angina. These two indications may make it difficult in an observational study to determine whether beta-blockers may prevent coronary disease in patients with high blood pressure. We discuss here our current thinking about the best analytic approach to this problem.