Introduction: The technological and scientific progress performed in the Human Proteome Project (HPP) has provided to the scientific community a new set of experimental and bioinformatic methods in the challenging field of shotgun and SRM/MRM-based Proteomics. The requirements for a protein to be considered experimentally validated are now well-established, and the information about the human proteome is available in the neXtProt database, while targeted proteomic assays are stored in SRMAtlas. However, the study of the missing proteins continues being an outstanding issue. Areas covered: This review is focused on the implementation of proteogenomic methods designed to improve the detection and validation of the missing proteins. The evolution of the methodological strategies based on the combination of different omic technologies and the use of huge publicly available datasets is shown taking the Chromosome 16 Consortium as reference. Expert commentary: Proteogenomics and other strategies of data analysis implemented within the C-HPP initiative could be used as guidance to complete in a near future the catalog of the human proteins. Besides, in the next years, we will probably witness their use in the B/D-HPP initiative to go a step forward on the implications of the proteins in the human biology and disease.