Separate volumes, several of them, can be written about the three phosphorylated residues that have rightly been the center of attention of canonical phosphoproteomics over the past three decades. We focus only of the consequences of introduction of these chemically stable phosphomonoester linkages. They reach an estimated ∼270 000 residues in the human proteome, add dianionic tetrahedral –PO₃²⁻ groups at multiple sites in proteins to drive conformational and functional changes that mediate the major flux of protein-based signal transduction in eukaryotic cells. Because the phosphate ester groups in P-Ser, P-Thr, and P-Tyr residues are so stable, families of chemoselective phosphoprotein phosphatases have evolved to counterbalance the action of canonical protein kinases and control the moment to moment phosphorylation state and thereby the information content of cellular signaling networks.