This chapter discusses the immune system of mice lacking the conventional major histocompatibility complex (MHC) class II molecules. Class II α : β dimers are known to be central regulators of the immune response, implicated in antigen presentation, T–B cell collaboration, and thymic education. Although most immunologists acknowledge the role of Class II α : β dimers in these diverse processes, they still argue over the precise mechanisms involved. In addition, there are some discussion over possible roles in other phenomena inside and outside the immune system—namely, an influence on class I restricted T cell responses, on the selection of the γ: δ T cell repertoire, on the differentiation of B cells, and on the maturation or targeting of sperm. To provide a new approach for resolving some of these controversies, three groups have produced mice with directed mutations in MHC class II loci; these mice are referred to as II 0 mice. There are four murine class II genes of known function—A α , A β , E α , and E β —and their products are considered to be the conventional class II molecules. A variety of criteria are used to establish that the II 0 mice are indeed devoid of conventional MHC class II molecules—cytofluorimetric, immunohistological, biochemical, and functional. When bred under specific-pathogen-free conditions, these animals thrive. However, if housed in a conventional facility, they can display a subnormal growth rate, health status, and breeding performance.