Contrary to widespread belief, the regulation and mechanism of degradation for the mass of intracellular proteins (i.e. differential, selective protein turnover) in vertebrate tissues is still a major biological enigma. There is no evidence for the conclusion that ubiquitin plays any role in these processes. The primary function of the ubiquitin-dependent protein degradation pathway appears to lie in the removal of abnormal, misfolded, denatured or foreign proteins in some eukaryotic cells. ATP/ubiquitin-dependent proteolysis probably also plays a role in the degradation of some so-called 'short-lived' proteins. Evidence obtained from the covalent modification of such natural substrates as calmodulin, histones (H2A, H2B) and some cell membrane receptors with ubiquitin indicates that the reversible interconversion of proteins with ubiquitin followed by concomitant functional changes may be of prime importance.