Knowledge of the applications of biochemistry, molecular biology, and genetics in the practice of medicine has been and continues to be a vital part of medical students' and continuing education. The technical background and the rapid expansion of information and new applications have made it an arduous task to learn and teach this material within the already crowded medical school curriculum. Problem-based learning (PBL) formats are rapidly being adopted at all levels of education as not only a major paradigm shift in education but also a solution for the instruction of biochemistry in medical school. Designing an effective biochemistry curriculum with PBL-based or lecture-based formats requires an appreciation for their strengths and weakness. The author's experiences in the Double Helix Curriculum at the University of Rochester School of Medicine and Dentistry (which employs PBL cases and complementing lectures) has shown that students are excited about learning in the PBL environment and explore in depth ways of integrating biochemistry, cell biology, genetics, and molecular biology into the practice of medicine. At the same time, complementary lectures greatly enhance uniformity in the quality and, importantly, the accuracy of the students' learning.