In nearly every multifactorial human disease, there are three periods that characterize our understanding and definition. First, there is a period in which there is rapid accumulation of descriptive data. Second, there is a longer and slower period as information is obtained that redefines and expands basic and clinical knowledge that lacks the final and important area of understanding aetiology and therapeutic intervention. Third, which is much less common for most diseases, is the vigorous definition of pathobiology and treatment. These phases are well illustrated by our current understanding of primary biliary cirrhosis (PBC). The term PBC was first used nearly 60 years ago and for the first 40 or so years, the primary research efforts were directed at clinical definitions and pathology. Subsequently, with the advent of molecular biology, there began a rigorous dissection of the immune response and, in particular, a better understanding of anti-mitochondrial antibodies. These efforts have greatly helped in our understanding of not only the effector mechanisms of disease, but also the uniqueness of the primary target tissue, biliary epithelium. However, this research has still not led to successful translation for specific therapy.