Historically, a principal reason Western medicine has progressed to the degree it has is the epistemology used to defne disease. Diseases are distinguished by two main methods: (1) assembly of defning characteristics (symptoms, physical descriptions both direct and derived from imaging techniques, and laboratory fndings and clinical course) that recur so as to form a clinical template and (2) assessment of cause and effects of the clinically defned disease. The method was frst clearly established in the nineteenth century with the defnition of microbial diseases and received its second great impetus with the development of molecular genetics. Although the pattern has been altered in more recent times with the development of science leading to the defnition of disease, a study of the classical methodology has a clear place in the study of disease. The history of the development of understanding of paroxysmal nocturnal hemoglobinuria is an excellent example of this methodology at work. In the present paper, I will emphasize the investigation of the causes and effects and show how these investigations have played a crucial role in the defnition of the disease and the understanding of the clinical manifestations.