Electron microscopy (EM) is the only technique that can combine sensitive protein-detection methods with detailed information on the substructure of cellular compartments. The purpose of this chapter is to describe some of the methods at the EM level that can be used to analyze the spatial organization of cell organelles with respect to phagosomes or vacuoles in which pathogens are sequestered, characterize the compartment in which pathogens are harbored, ie immature phagosomes, phagolysosomes, autophagosomes, and ER-derived vacuoles, to cite a few, and decipher the molecular mechanisms involved in survival of pathogens within infected host cells.