The completion of the human and mouse genome projects at the beginning of the past decade represented a very important step forward in our pursuit of a comprehensive understanding of the genetic control of mammalian development. Nevertheless, genetic analyses of mutant phenotypes are still needed to understand the function of individual genes. The genotype-based approaches, including gene-trapping and gene-targeting, promise a mutant embryonic stem (ES) cell resource for all the genes in mouse genome; however, the phenotypic consequences of these mutations will not be addressed until mutant mice are derived from these ES cells, which is not trivial. An efficient and non-biased, N-ethyl-N-nitrosourea (ENU)-based forward genetic approach in mouse provides a unique tool for the identification of genes essential for development and adult physiology. We have had great success in identifying genes essential for morphogenesis and early patterning of mouse via this approach. Combined with complete genome information and numerous genetic resources available, ENU-based mutagenesis has become a powerful tool in deciphering gene functions.