Immediate early response gene X‐1 (IEX‐1) or immediate early response 3 is an immediate early response gene that is highly expressed in epithelial, endothelial, and immune cells, including macrophages.1, 2, 3, 4 Similar to other immediate early response genes, its induction can be rapidly induced in response to several stimuli, such as UV light, inflammatory cytokines, and mechanical strain.4, 5, 6, 7, 8 Under stress, many immediate early response genes, such as c‐Fos, c‐Jun, c‐Myc, Egr‐1, and other zinc‐finger proteins, usually serve as transcription factors, activators, or repressors to regulate the transcriptional activity of several genes that are critical for a cell to appropriately respond to stress.4, 9, 10, 11, 12 However, IEX‐1 lacks a DNA binding domain and its putative transcription activity remains elusive.4, 13 Investigations from our laboratory show that IEX‐1 controls mitochondrial superoxide production by regulating the electron transport chain and oxidative phosphorylation.13, 14, 15, 16 This action of IEX‐1 might explain the transcriptional activity associated with IEX‐1 because the reactive oxygen species (ROS) at low levels can act as a signaling molecule to alter gene transcription through reduction‐oxidation–sensitive transcription factors or a signaling pathway, such as nuclear factor‐κB (NF‐κB) and nuclear factor erythroid 2‐related factor.17, 18, 19 Consistent with a key role of mitochondria in vascular and metabolic functions, IEX‐1 deficiency impairs vascular function and increases energy expenditure in mice. A key role of IEX‐1 in regulation of mitochondrial respiration and ROS production may also help to explain how IEX‐1 produces both antiapoptotic and proapoptotic actions in different cell types. Macrophages, the central player in the pathogenesis of many chronic inflammatory conditions, express high levels of IEX‐1. In agreement with the putative role of IEX‐1 in macrophage function, we recently identified a crucial role of IEX‐1 in many chronic conditions, including hypertension, sepsis, insulin resistance, obesity, and arthritis,16, 20, 21, 22 revealing previously unknown functions of IEX‐1 in cardiovascular and metabolic diseases. In this article, we reviewed the findings in IEX‐1 knockout mice from our laboratory and others and primarily focused on the roles of IEX‐1 in cardiovascular and metabolic disorders. We also alluded to the important findings from other laboratories that are relevant for its role in cardiovascular and metabolic diseases. In addition, an attempt is made to underline the involvement of IEX‐1 in inflammation and its possible link with the lipid‐mediated metabolic diseases. However, because of the limitations and scope of this article, we refrained from discussing an important role of IEX‐1 in many types of cancers that has been widely reported before.