Over the past 10 years, there has been a remarkable increase in the use of LC-MS for the quantitative determination of proteins, and this technique can now be considered an established bioanalytical platform for the quantification of macromolecular drugs and biomarkers, next to the traditional ligand-binding assays. Many researchers have contributed to the field and helped improve both the technical possibilities of LC-MS-based workflows and our understanding of the meaning of the results that are obtained. As a tribute to , which has published many important contributions, this report gives a high-level overview of the most important trends in the field of protein LC-MS, as published in this journal since its inauguration a decade ago. It describes the major technical developments with regard to sample handling, separation and MS detection of both digested and intact protein analysis. In addition, the relevance of the complex structure and behavior of proteins is discussed and the effect of protein-protein interactions, biotransformation and the occurrence of isoforms on the analytical result is addressed.