The traditional overarching concept of disease pathogenesis entails the natural history of disease, i.e. the concept that any disease is a unified entity from beginning to termination. The concept of the natural history of disease encourages researchers and clinicians alike to conceptualize all clinical signs and symptoms in a patient as manifestations of a single disease process. Our experiences in dissecting the genetic control of autoimmune diseases and autoimmune phenotypes sugges that for many autoimmune processes, an alternative conceptual framework may be more useful. We term this approach a “modular” theory of autoimmunity. “Modules” are distinct, genetically controlled clinical or pathological phenotypes which can interact to construct a disease process. Modules may interact additively, synergistically, or antagonistically in any given individual. Multiple modules can coexist and produce unique disease phenotypes. We illustrate this concept with examples from the murine autoimmune model of type one diabetes, the nonobese diabetic (NOD) mouse.