Reference proteomes are generated by increasingly sophisticated annotation pipelines as part of regular genome build releases; yet, the corresponding changes in reference proteomes' content are dramatic. In the history of the NCBI-curated human proteome, the total number of entries Journal of Bioinformatics and Computational Biology Vol. 10, No. 6 (2012) As an application example, we show that the proteome°uctuations a®ect the interpretation (about 74% of hits) of organelle-speci¯c mass-spectrometry data. Although proteome quality tends to improve with more recent releases as, for example, the fraction of proteins with functional annotation has increased over time, existing evidence implies that, apparently, the proteome content still remains incomplete, not just pertaining to isoforms/sequence variants but also to proteins and their families that are clearly distinct.