Mice are increasingly being used as models for the study of various human diseases. This is primarily because among mammalian modals, they are most amenable to genetic manipulations. As we attempt to understand the molecular mechanism of diseases, it is imperative that the genes involved in the disease process be identified. One approach is to study mouse mutants with symptoms analogous to human diseases, and try to identify the genes responsible. Another approach is to manipulate the expression of genes suspected to be involved and see how they affect the disease development. This review briefly discusses the concept of manipulating gene expression by transgenic and gene knockout technology and illustrates this with how these technique are used to study the mechanism of diabetic complications.