Although cells of the innate immune response have a variety of pattern recognition receptors that are triggered by blood classes of markers, a critical feature of the adaptive immune response is antigenic specificity. Yet it is becoming increasingly clear that the specificity of lymphocyte receptors admits of some laxity. Cross-reactivity may, in fact, be necessary for lymphocyte survival as antigen receptor signaling maintains cellular viability in the absence of antigen activation. Studies of molecular mimicry have revealed many instances in which antibodies to microbial antigens bind also to self-antigens; in some cases, this cross-reactivity has pathogenic potential. In this chapter, we describe cross-reactivity between two self-antigens, DNA and NMDA receptors, and how antibodies with specificity for DNA in patients with splenic lupus may cause central nervous system damage by virtue of binding also to neuronal receptors. This example serves as a reminder that cross-reactivity may exist among self-antigens as well as between foreign and self-antigens.