Dioxygenases belong to one of the three major classes of heme-based enzymes that utilize atmospheric O2 as a substrate. Oxidases, such as cytochrome c oxidase, reduce O2 to two water molecules by utilizing four electrons and four protons, and harness the redox energy to pump four protons across the protein matrix. Monooxygenases, such as P450, convert one atom of dioxygen to a water by consuming two electrons and two protons, and exploit the redox energy to insert the other oxygen atom into an organic substrate. Dioxygenases, including tryptophan dioxygenase (TDO) and indoleamine 2,3-dioxygenase 1 (IDO1), are unique, and least understood, as they are capable of inserting both atoms of O2 into Trp without using any electrons and protons. In Part A of this chapter, we review the structure and function relationships of human TDO and IDO1 and compare them with those of bacterial TDOs and two dioxygenase analogs, PrnB and MarE. In Part B we outline the mechanisms by which the TDO and IDO1 functions are regulated in vivo by a variety of effectors under various (patho)physiological conditions.