The study of the genetic code has collectively revealed that the biochemical basis of heredity is uniform for nearly all known forms of life. Genetic approaches have generated a much better appreciation and understanding of many aspects of biological processes-and in some cases provided strategies for the treatment of human diseases. Still, the enormous and undoubtedly impressive amount of information gathered on gene sequences, their myriad expression patterns and translation into proteins is insufficient to answer seemingly simpler questions such as to what sets us humans apart from much more undemanding species while sharing almost the same sets of genes. Regulation of the proteome by post-translational modifications (PTMs) is beginning to be understood as a major contributing factor to the structural and functional diversity in biology and for defining cellular mechanisms in particular. Covalent, PTMs provide an astonishingly rich and specific basis for an ultrafast regulation of cellular processes, many of which converge to transcription units to control gene expression. With this essay we intend to share with the reader the rapid growth of our knowledge of the many conjunctions that exist between PTMs and key cellular processes that have emerged by studying the nuclear receptors (NRs) and their transcriptional coregulators.