This proposal requests partial funding in support of the five forthcoming Gordon Research Conferences on Three-Dimensional Electron Microscopy of Macromolecules (3DEM) in the 2008 to 2012 period, to continue this most successful series. The impact of the preceding 13 meetings has been such that the 3DEM community has come to regard this Gordon Conference as the most important scientific event in the field. Electron microscopy (EM) is unique in addressing questions in structural molecular and cell biology that are not accessible by other methods. EM is increasingly able to deliver near-atomic resolution of biological macromolecules and their assemblies, such as viruses or amyloid fibrils that are of exceptional medical importance. Moreover, the method is uniquely able to image these objects and assemblies in their cellular context by electron tomography. EM is the essential bridge between light microscopy that operates at cellular and sub-cellular resolution of living cells on the one hand, and X-ray crystallography or NMR on the other, which provide atomic detail of their molecular components. Recent technical developments enable threedimensional structures of macromolecular assemblies to be determined with ever increasing accuracy, and under different, functionally relevant physiological conditions. As a result, there are unprecedented new opportunities for understanding basic molecular mechanisms in health and disease, biomedically important interactions between macromolecules and the principles of bio-molecular design. Imminent technical breakthroughs in EM will result in substantial improvements of instrument performance, and a very significant expansion of the scope of 3DEM in biology and medicine. These new developments will be explored in the forthcoming meetings. The next 5 meetings of the 3DEM Gordon Conference are certain to play a central role in defining new technical challenges for the next decade, and in a concerted effort to apply EM for a better understanding of fundamental biomedical questions. ? ? ?