The aim of our study was to outline and present the major hallmarks in the history of clinical cytology. For this purpose, an extensive research in modern literature and the PubMed database was undertaken. Furthermore, we studied original papers and books of the pioneers in cytopathology. The development of the first microscope by Hans and Sacharias Janssen is a hallmark in biological sciences, since the study of microcosmos was made feasible. From the discovery of single cells by Robert Hooke and the cell theory by Schleiden and Schwann till the establishment of exfoliative cytology by George Papanicolaou and the invention of fine-needle aspiration biopsy technique by Martin and Ellis, there is a three-century continuum of important discoveries and research. Today, flow cytometry and the introduction of molecular techniques have revolutionized medicine and are expected to change the face of cytology in the near future. Diagn. Cytopathol. 2012; © 2012 Wiley Periodicals, Inc.