Recent development of knockout mice with targeted deletion of specific genes encoding various red cell membrane proteins has added valuable armamentarium to red cell membrane structure-function studies. In this chapter we will summarize the various recent developments regarding the structure and function of the red cell membrane derived from studies using knockout mice. In addition to being expressed in red cells, all major red cell membrane proteins are also expressed in cells of various tissues. The potential use of knockout mice to decipher the biological functions of red cell membrane proteins in non-erythroid cells is also explored.