The ultimate goal of cell biology is to understand how all of the many different sorts of molecular machines in the living cell operate in situ, and ultimately, to understand how the concerted activity of all these machines is coordinated or integrated into a whole, to create the behavior of the living cell. Electron microscopy can help to answer these questions, if it can reach the level of resolving individual macromolecules in whole cells, and if it can reach this level of resolution without at the same time introducing gross distortions in the arrangement of these molecules or in the architecture of the cell's cytoplasm, in general. The aim of this article is to compare and contrast the two major approaches that electron microscopists are using today, in their efforts to achieve this broad, ambitious goal.
Biomedical Reviews 2001; 12: 11-29.
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