While utilization of structural information has been a staple technology in drug discovery for many years, electron microscopy creates opportunities that have been thus far out of reach for the conventional techniques, like the visualization of very large molecular complexes in solution or obtaining high-resolution structural data for small molecules from microcrystals. These opportunities come at a cost: hardware is extremely expensive, software is ever-changing, and constantly challenged by new developments in the hardware and requests by the users, and IT departments are faced with significant requirements for storage and computational power. Nevertheless, the establishment of centralized facilities, commercial consortia, and cooperative research centers is well positioned to provide access to Cryo-EM to an expanded base of researchers, from academia as well as from industry. Understanding of the requirements, advantages, and limitations of this technique becomes then necessary to ensure correct decision-making processes and resource allocation when undertaking a structure-guided drug design project.