Human diseases have historically been classified on the basis of their end-organ manifestations, using a traditional clinicopathological approach dating to the 19th century. With the advent of rigorous molecular methodologies at the end of the 20th century, many specific disease determinants were identified and more targeted therapeutic strategies developed. Although the conventional reductionist approach underlying these strategies for understanding disease served us well in the pregenomic era, it hampers our understanding of the complex molecular networks within which disease develops that are increasingly manifest in the current era. This article presents a novel, holistic method for classifying human diseases that can serve as a template for understanding disease pathobiology, prognosis, and treatment.