Homology-driven proteomics aims at exploring the proteomes of organisms with unsequenced genomes that, despite rapid genomic sequencing progress, still represent the overwhelming majority of species in the biosphere. Methodologies have been developed to enable automated LC-MS/MS identifications of unknown proteins, which rely on the sequence similarity between the fragmented peptides and reference database sequences from phylogenetically related species. However, because full sequences of matched proteins are not available and matching specificity is reduced, estimating protein abundances should become the obligatory element of homology-driven proteomics pipelines to circumvent the interpretation bias towards proteins from evolutionary conserved families.