This 2012 Annual Review Issue of The Journal of Pathology argues strongly that cell biology, in its many disciplines, underpins the foundation of our understanding of the mechanisms of disease—the holy grail of pathology. Our increasing knowledge of the human genome will not be enough to attain this goal without parallel developments in our comprehension of the results, at the cellular level, of these genetic changes. In the end, it is cell biology and cell biologists who will deliver this mission. Copyright © 2011 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.