The immune self is one of the main organizing concepts in immunology. However, it is not quite clear what the immune self is and heated debates have taken place among immunologists concerning the meaning and usefulness of this concept. In this chapter, I further illustrate the benefits of a meaning-making perspective and argue that the problem of the immune self can be approached as analogous to the problem of finding the different senses of the sign in semiotics. Following this suggestion, I would like to present the idea that the immune system is a meaning-making system and in this context to provide a novel conceptualization of the immune self that integrates several ideas from immunology and semiotics.