Eryptosis is a tightly regulated form of programmed cell death, crucial for maintaining erythrocyte count in body circulation. Eryptosis is a physiological phenomenon however, when dysregulated or excessively activated, eryptosis can become pathogenic. For instance, in pathological conditions such as diabetes, chronic kidney disease (CKD), sepsis, malaria, and hemolytic anemia, premature removal of erythrocytes occurs, contributing to the development of anemia. Eryptosis is characterized by key cellular changes, including the externalization of phosphatidylserine (PS), cell shrinkage, and membrane blebbing. The primary inducers of eryptosis include increased oxidative stress, hyperosmolarity, energy depletion, and xenobiotic exposure. All these stressors somehow contribute to an influx of Ca2+ ions in erythrocytes. The subsequent elevation in cytosolic Ca2+ activates several signaling pathways, which result in cell shrinkage, membrane blebbing, and phosphatidylserine externalization, thus disrupting the integrity of the erythrocyte plasma membrane (shown in the flowchart diagram). These stressors also activate various kinases and signaling molecules, including p38 mitogen-activated protein kinase (MAPK), AMP-activated protein kinase (AMPKα), casein kinase 1α (CK1α), and cyclin-dependent kinase 4 (CDK4), which collectively mediate the progression of eryptotic pathways. Recent research has identified several new therapeutic targets to modulate eryptosis, which could be beneficial in managing disorders like anemia, sickle cell disease, or thalassemia. One such target is the inhibition of Ca2+ influx by using a calcium channel blocker like amlodipine, as increased intracellular calcium plays a pivotal role in initiating eryptosis. Inhibiting Ca2+-permeable ion channels, such as cation channels of the transient receptor potential (TRP) family, has shown promise in reducing premature erythrocyte death. Furthermore, oxidative stress and phosphatidylserine exposure on the outer membrane of erythrocytes are hallmarks of eryptosis, and modulating the activity of enzymes like phospholipid scramblase or reducing ROS levels by using scavengers (antioxidants) is emerging as a potential therapeutic strategy. Inhibition of the ceramide pathway is one promising area as it is involved in the regulation of erythropoietin signaling, which plays a pivotal role in erythropoiesis. To assess whether erythrocytes are undergoing eryptosis, various diagnostic parameters are utilized, such as the detection of phosphatidylserine exposure via flow-cytometry using Annexin V-FITC, the measurement of intracellular Ca²⁺ levels using calcium-sensitive fluorescent dyes, the quantification of reactive oxygen species (ROS) through DCFDA staining, morphological alterations via microscopic examination, and the detection of ceramide accumulation using immune-staining or mass spectrometry techniques. Regulation of eryptosis and erythrocytes count is crucial to prevent adverse outcomes associated with excessive erythrocyte death.