In most U.S. and Canadian medical schools, pharmacology is taught during the preclinical year 2 of the 4-year-long curriculum. This is despite the fact that medical school graduates and residency directors have identified teaching rational therapeutics as a priority. Hence, we have developed a core curriculum in clinical pharmacology for 4th-year medical students that builds on the core principles of rational therapeutics described by Nierenberg 10 years ago (Nierenberg, DW. Clin Pharmacol Ther 1990; 48:606-610). Here we report on our 3-year experience teaching this course, which addresses the following teaching objectives: to teach medical students on how to (1) critically evaluate medications; (2) obtain a complete medication history including herbal and over-the-counter medications; (3) apply pharmacokinetic principles to clinical practice; (4) recognize and report adverse drug events and interactions; (5) optimize pain management; (6) recognize and treat substance abuse and poisoning; and (7) prescribe rationally regardless of prescribing environment. Student assessment was in the form of multiple-choice and formative oral examinations, which were validated against the clinical part of the U.S. medical licensing examination. The course significantly increased the student rating of clinical pharmacology teaching measured by a national survey of U.S. medical school graduates. We conclude that this course may be useful for teaching rational prescribing to medical students. With the guidance and educational material provided by this article, a successful implementation of such a course should be possible in most medical schools.