AbstractAlthough Fischer's extraordinary career came to focus mostly on the protein phosphatases, after his co‐discovery of Phosphorylase Kinase with Ed Krebs he was clearly intrigued not only by cAMP‐dependent protein kinase (PKA), but also by the heat‐stable, high‐affinity protein kinase inhibitor (PKI). PKI is an intrinsically disordered protein that contains at its N‐terminus a pseudo‐substrate motif that binds synergistically and with high‐affinity to the PKA catalytic (C) subunit. The sequencing and characterization of this inhibitor peptide (IP20) were validated by the structure of the PKA C‐subunit solved first as a binary complex with IP20 and then as a ternary complex with ATP and two magnesium ions. A second motif, nuclear export signal (NES), was later discovered in PKI. Both motifs correspond to amphipathic helices that convey high‐affinity binding. The dynamic features of full‐length PKI, recently captured by NMR, confirmed that the IP20 motif becomes dynamically and sequentially ordered only in the presence of the C‐subunit. The type I PKA regulatory (R) subunits also contain a pseudo‐substrate ATPMg2‐dependent high‐affinity inhibitor sequence. PKI and PKA, especially the Cβ subunit, are highly expressed in the brain, and PKI expression is also cell cycle‐dependent. In addition, PKI is now linked to several cancers. The full biological importance of PKI and PKA signaling in the brain, and their importance in cancer thus remains to be elucidated.