After several decades of development, and a recent breakthrough in the quality of the recoding medium single-particle cryo-electron microscopy has joined X-ray crystallography as a major tool of molecular structure research. Beyond foregoing the need for crystallization, this technique offers distinct advantages over X-ray crystallography as it depicts the molecule in a functionally relevant conformation, and as it is capable of determining multiple states from the same sample. This lecture will trace the history of the development, particularly of concepts and computational realization. In my own lab, the ribosome has served as the main molecule to try out and demonstrate progress with the development of the technique. I will give examples of current capabilities and the potential for new insights relevant to Molecular Medicine as the 3-Angstrom barrier is now being crossed in many instances. In conclusion, I will sketch out new promising developments of single-particle cryo-EM, including time-resolved techniques and the mapping of a continuum of states. Literature: Frank, J. (2017). Advances in the field of single-particle cryo-electron microscopy over the last decade. Nature Protocols 12, 209-212. Frank, J. (2016). Generalized single-particle cryo-EM – a historical perspective. Microscopy 65, 3–8.