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Over the last twenty years, biomolecular scientists learned to switch from the model to the result, from a design based on a four letter alphabet to the final twenty letters based outcome of the genetic project. From genome to the proteome. This important step was taken because the evolutive information is carried by a very rigid molecule, the DNA, and becomes effective in much more flexible objects, the proteins, whose chemical and physical freedom supports every life process. “Proteomics” is a relatively newborn science, whose aim is to study the entire complement of proteins produced by an organism. No other science has attracted such an impressive amount of human, technological and economic resources among the large field of biochemical research over the last decade, because proteins are involved in every biological process. Scientific research against any known disease has one or more protein as final target. If any living being can be considered as an envelope protecting its most important treasure, the genetic information, then proteins must be thought as both results of the information and tools for protecting, conserving and passing it on. In this point of view, “proteomics” is not just that somewhat mysterious core facility down the building, where “upstair” scientists bring their samples just to know “who's in that 2D gel spot”. Proteomics is putting every protein in place in its correct biochemical contest, assessing its identity, its modifications map, its degree of over or underexpression, its folding and its interactions with other proteins. In this extremely ambitious project, mass spectrometry plays a crucial role, because the development of electrospray and MALDI ion sources (John B. Fenn and Koichi Tanaka, Nobel laureates in 2002) opened a brand new world, where even molecular “elephants” can be transferred in the gas phase, opening unique and almost endless possibilities for protein analysis. The aim of this special issue, composed of eight reviews, is to give the reader an introductory but exhaustive overview of the analytical techniques used to purify, identify, quantify and characterize proteins, keeping the main focus on mass spectrometry. The first two articles have been written by William Ward and Gert Van Den Berg, acknowledged experts on protein purification and 2D gel electrophoresis, respectively. These two steps are the foundation of the MS-based protein research, because they allow a protein to be purified from its biological environment, an extremely complex analytical matrix. The third review describes how a protein can be identified, through a “bottom-up” process and the extensive use of bioinformatics tools, whose key role in proteomics is to extract significant results from the enormous amount of data generated by mass spectrometry. This last topic is covered by a notable review of Michael Goshe. Post translational modifications of proteins, such as phosphorylations and glycosilations, play a crucial role in their biological activity and are one of the most addressed issues in proteomics. In his review, Willy Morelle exhaustively describes the most important techniques for PTMs analysis. The fifth article, written by Michael Goshe again, brightly describes an array of relatively new tools for quantitative proteomics, based on both label and label-free methods. The last two papers deal with an area of protein science that is not usually included (unfortunately) in classical MS-based “proteomics” reviews. These two articles focus on a frontier area of mass spectrometry: the study of protein structure, folding and function. Such an exciting field of research is greatly discussed by Lars Konermann and John Engen. The Authors and the Editor sincerely hope that this special issue will represent an outline of the state of the art of several fields of proteomic sciences, possibly representing an introductory approach for those analytical scientist not (yet?) directly involved in protein research. Finally, as Guest Editor of this special issue I would like to express my gratitude to the Authors for their excellent work and to the Publishers for giving me the opportunity to work with such a brilliant group of scientists.