Essential for Reactive Oxygen Species (EROS) protein, encoded by the Cytochrome b Chaperone 1 (CYBC1) gene binds directly to the gp91phox subunit of the phagocyte NADPH oxidase (NOX2) and is essential for its stability. When EROS is absent, there is extremely low abundance of the gp91phox-p22phox heterodimer, leading to loss of reactive oxygen species production and a form of chronic granulomatous disease (CGD), CGD type 5 (CGD5). However, EROS can also control the abundance of a select group of other proteins, including the ATP-gated cation channel P2X7, a member of the purinergic family of receptors that is highly expressed on macrophages. EROS can be thus seen as a highly specific chaperone protein, but recent studies suggest it may also regulate the electron transfer process in reactive oxygen species (ROS) generation. Our work on this fascinating protein started with interrogating the physiological role of a gene of unknown function (bc017643 in mouse, C17ORF62 in human). It was prompted by the observation that mice deficient in bc017643 were highly susceptible to Salmonella Typhimurium. We will describe how we demonstrated that bc017643 encoded this highly specific chaperone/assembly factor in both mouse and human. The description of the initial characterization and subsequent observations will be in the form of a first-person account (DCT), and we will then move on to key unanswered questions in the biology of EROS and its implications for the phagocyte NADPH oxidase more generally (EKT and DCT).