One of the surprises from genome sequencing projects is the apparently small number of predicted genes in different eukaryotic cells, particularly human. One possible reason for this ‘shortage’ of genes is multiple distribution of proteins; a single protein is targeted to more than one subcellular compartment and consequently participates in different biochemical pathways and might have completely different functions. Indeed, in recent years, there have been reports on proteins that were found to be localized in cellular compartments other than those (...) initially attributed to them. Furthermore, the phenomenon of highly uneven isoprotein distribution was recently observed and termed ‘eclipsed distribution’. In these cases, the amount of one of the isoproteins, in one of the locations, is significantly minute and its detection by standard biochemical and visualization methods is masked by the presence of the dominant isoprotein. In fact, the minute amounts of eclipsed proteins can be essential. Since detecting eclipsed distribution is difficult, we assume that this phenomenon is probably more common than currently recorded. Hence, developing methods for localization and functional detection of eclipsed proteins is a challenge in cell biology research. Finally, eclipsed distribution may lead to cellular pathologies as has been suggested to occur in human disorders such as Prion diseases and Alzheimer. This review provides a short description of the eclipsed distribution phenomenon followed by an overview of protein distribution mechanisms, examples of eclipsed distribution and experimental approaches for revealing these elusive proteins. BioEssays 29:772–782, 2007. © 2007 Wiley Periodicals, Inc.. (shrink)