Heme is an essential biomolecule and cofactor that participates in many different biological processes by binding to a diverse group of proteins to affect structure, function, and regulation. Yet, heme becomes toxic to human cells when its levels are elevated. As will be the focus of this review, the major route of heme detoxification in humans is through the heme degradation pathway involving heme oxygenase (HO). Humans, as well as other amniotes, express two isoforms of HO, HO1 and HO2, and understanding the role each isoform plays in regulating heme homeostasis is of great interest. Recently, a role for HO2 in sequestering, rather than degrading, heme has been uncovered. Here, we highlight this role of HO2 and place it in context of how, when, and why heme degradation proceeds, including the regulation of HO activity by the other necessary components of the reaction: oxygen and electrons from NAPDH via cytochrome P450 reductase. In addition, we review the significant roles the products of heme degradation (biliverdin, iron, and carbon monoxide) play in human health. Therefore, HO has many spheres of influence centered around substrates and products of the reaction, signifying the wide-reaching effects of heme degradation and sequestration.