Cryo-electron microscopy (cryo-EM) of non-crystalline single particles is a biophysical technique that can be used to determine the structure of biological macromolecules and assemblies. Historically, its potential for application in drug discovery has been heavily limited by two issues: the minimum size of the structures it can be used to study and the resolution of the images. However, recent technological advances — including the development of direct electron detectors and more effective computational image analysis techniques — are revolutionizing the utility of cryo-EM, leading to a burst of high-resolution structures of large macromolecular assemblies. These advances have raised hopes that single-particle cryo-EM might soon become an important tool for drug discovery, particularly if they could enable structural determination for 'intractable' targets that are still not accessible to X-ray crystallographic analysis. This article describes the recent advances in the field and critically assesses their relevance for drug discovery as well as discussing at what stages of the drug discovery pipeline cryo-EM can be useful today and what to expect in the near future.

非晶单颗粒的低温电子显微镜（cryo-EM）是一种生物物理技术，可用于确定生物大分子和组装体的结构。从历史上看，它在药物发现中的应用潜力受到两个问题的严重限制：可用于研究的结构的最小尺寸和图像的分辨率。但是，最近的技术进步（包括直接电子检测器的发展和更有效的计算图像分析技术）正在革新cryo-EM的实用性，导致大型高分子组装体的高分辨率结构的爆发。这些进展使人们寄希望于单粒子cryo-EM可能很快成为药物发现的重要工具，尤其是如果它们能够实现“ 难以进行X射线晶体学分析的难处理目标。本文介绍了该领域的最新进展，并严格地评估了它们与药物发现的相关性，并讨论了在药物发现管道的哪些阶段，cryo-EM在今天可能有用，并在不久的将来会有用。