Inspired by some preliminary data and their versatile chemistry we have been investigating the ability of porphyrins to inhibit proteasome activity. Cationic porphyrins exhibit an amazing variety of binding modes and inhibition mechanisms. They may bind to the 20S proteasome gates hindering the entrance of the substrate into the catalytic chamber or, by functional connection between the α- and β-rings, allow for allosteric modulation. By contrast, anionic porphyrins may activate the core particle by facilitating the access of the substrate to the proteasome interior, likely regulating the “open”-“closed” allosteric equilibrium. In conclusion, the positioning of the charged substituents represents a sort of key code to fine-tuning porphyrins interference with proteasome gating.