Activating transcription factor 4 (ATF4) is a DNA binding transcription factor belonging to the family of basic Leucine zipper proteins. ATF4 can be activated in response to multiple cellular stress signals including endoplasmic reticulum stress in the event of improper protein folding or oxidative stress because of mitochondrial dysfunction as well as hypoxia. There are multiple downstream targets of ATF4 that can coordinate the regulation between survival and apoptosis of a cell based on time and exposure to stress. ATF4, therefore, has a broad range of control that results in the modulation of immune cells of the innate and adaptive responses leading to regulation of the cellular immunity. Studies provide evidence that ATF4 can regulate immune cells such as macrophages, T cells, B cells, NK cells and dendritic cells contributing to progression of disease. Immune cells can be exposed to stressed environment in the event of a pathogen attack, infection, inflammation, or in the tumor microenvironment leading to increased ATF4 activity to regulate these responses. ATF4 can further control differentiation and maturation of different immune cell types becoming a determinant of effective immune regulation. Additionally, ATF4 has been heavily implicated in rendering effector immune cells dysfunctional that are used to target tumorigenesis. Therefore, there is a need to evaluate where the literature stands in understanding the overall role of ATF4 in regulating cellular immunity to identify therapeutic targets and generalized mechanisms for different disease progressions.