TP53-induced glycolysis and apoptosis regulator (TIGAR) is crucial for generating NADPH. As a Tp53 target gene, TIGAR contains a bisphosphatase domain that resembles that of 6-phosphofructo-2-kinase/fructose 2,6-bisphosphatase (PFKFB). TIGAR primarily resides in the cytoplasm, but when faced with stress, it moves to the nucleus and various organelles like mitochondria and the endoplasmic reticulum to control cell activities. TIGAR transcription is regulated by Tp53 family members (p53, p63, and p73), along with certain transcription factors (Sp1 and CREB) and non-coding microRNAs (miRNAs) (miR-144, miR-146a-5p, miR-101, miR-652-5p, and miR-885-5p). TIGAR hydrolyzes fructose 1,6-bisphosphate and fructose 2,6-bisphosphate to inhibit glycolysis. It also enhances the flow of PPP to generate NADPH and ribose, consequently aiding in DNA repair and lowering intracellular ROS levels. Thus, TIGAR helps sustain equilibrium in energy metabolism, control autophagy and stem cell differentiation, and enhance cell viability. Simultaneously, it also plays a noncatalytic role in stabilizing the retinoblastoma protein (RB) and interacting with nuclear factor-erythroid 2-related factor 2 (Nrf2), hexokinase 2 (HK2), mitochondrial complex V component ATP5A1, nuclear factor kappa B (NF-κB), and succinate dehydrogenase to regulate both cell cycle arrest and inflammatory reactions and preserve mitochondrial function. TIGAR could be a promising focus for the prevention and management of heart and brain conditions as well as cancer.