<p>Two related classes of ligand-binding heme <i>c</i>-containing proteins with a high degree of structural homology have been identified and characterized over recent decades: cytochromes P460 (cyts P460), defined by an unusual heme-lysine cross-link, and cytochromes <i>c</i>′-β (cyts <i>c</i>′-β), containing a canonical <i>c</i>-heme without the lysine cross-link. The shared protein fold of the cyt P460-cyt <i>c</i>′-β superfamily can accommodate a variety of heme environments with entirely different reactivities. On the one hand, cyts P460 with polar distal pockets have been shown to oxidize NH₂OH to NO and/or N₂O via proton-coupled electron transfer. On the other hand, cyts <i>c</i>′-β with hydrophobic distal pockets have a proposed gas binding function similar to the unrelated, but more extensively characterized, alpha helical cytochromes <i>c</i>′. Recent studies have also identified ‘halfway house’ proteins (cyts P460 with non-polar heme pockets and cyts <i>c</i>′-β with polar distal heme pockets) with functions yet to be resolved. Here, we review the structural, spectroscopic and enzymatic properties of the cyt P460-cyt <i>c</i>′-β superfamily with a view to understanding the structural determinants of their different functional properties.</p> Graphical abstract <p></p>