Cleft lip and palate is the most common craniofacial birth defect, and its etiology has been the focus of many reports in the literature. It is well accepted that both genetics and environment play a role in the condition; however, the authors still have not been able to translate what have been learned into clinical applications. This paper provides an interpretation of 2 possible mechanisms leading to cleft lip and palate in humans. First, the authors reflect on the known association between maternal cigarette smoking and risk for cleft lip and palate and the proposed hypoxic mechanism put forward to explain this association. Second, the authors reflect on the difference in frequency between left and right cleft lip and propose that without more extensive clinical definitions, it will be difficult to definitely unveil genetic targets that can be used for counseling.