The laboratory mouse has become the model organism of choice in numerous areas of biological and biomedical research, including the study of congenital birth defects. The appeal of mice for these experimental studies stems from the similarities between the physiology, anatomy, and reproduction of these small mammals with our own, but it is also based on a number of practical reasons: mice are easy to maintain in a laboratory environment, are incredibly prolific, and have a relatively short reproductive cycle. Another compelling reason for choosing mice as research subjects is the number of tools and resources that have been developed after more than a century of working with these small rodents in laboratory environments. As will become obvious from the reading of the different chapters in this book, research in mice has already helped uncover many of the genes and processes responsible for congenital birth malformations and human diseases. In this chapter, we will provide an overview of the methods, scientific advances, and serendipitous circumstances that have made these discoveries possible, with a special emphasis on how the use of genetics has propelled scientific progress in mouse research and paved the way for future discoveries.