The combination of optical high resolution microscopy with electron microscopy brings together two extremely powerful imaging techniques. By localizing a fluorescently labeled molecule on a cellular object with confocal microscopy and then ultra-structurally resolving the object where the molecule itself is localised by EM (2D and 3D), CLEM will open avenues to structurally characterize new organelles and molecular machines. This procedure circumvents the necessity to immune-label EM thin sections, a method often prone to error and hence will provide many researchers with unprecedented contextual information of cellular nanostructures. Here we will discuss different CLEM applications, highlighting pros and cons of the various methods.