ICAMs play a crucial role in immune responses, intercellular adhesion, and communication. This review highlights the importance of ICAMs in signal transduction and their contributions to reciprocal cell signaling and function, particularly in processes where β2 integrins are thought to take the lead, such as T cell activation, differentiation, and migration. ICAMs, including ICAM-1, -2, and -3, are expressed by leukocytes and vascular endothelial cells and are involved in leukocyte activation and transendothelial migration. β2 integrins, such as LFA-1, Mac-1, and p150,95, bind to ICAMs, enabling leukocyte activation and transendothelial migration. The interaction between β2 integrins and ICAMs is essential for intracellular signaling, and recent studies support the role of ICAMs in this process. ICAMs are dynamic adhesion molecules associated with the actin cortex, and their functions are influenced by their linkage to the cytoskeleton. ICAMs also play a role in disease, including leukocyte adhesion deficiency, dry eye disease, cardiovascular disease, intestinal inflammation, pulmonary fibrosis, and autoimmunity. The study of ICAMs is important for understanding the pathogenesis of these diseases and for developing therapeutic strategies.ICAMs play a crucial role in immune responses, intercellular adhesion, and communication. This review highlights the importance of ICAMs in signal transduction and their contributions to reciprocal cell signaling and function, particularly in processes where β2 integrins are thought to take the lead, such as T cell activation, differentiation, and migration. ICAMs, including ICAM-1, -2, and -3, are expressed by leukocytes and vascular endothelial cells and are involved in leukocyte activation and transendothelial migration. β2 integrins, such as LFA-1, Mac-1, and p150,95, bind to ICAMs, enabling leukocyte activation and transendothelial migration. The interaction between β2 integrins and ICAMs is essential for intracellular signaling, and recent studies support the role of ICAMs in this process. ICAMs are dynamic adhesion molecules associated with the actin cortex, and their functions are influenced by their linkage to the cytoskeleton. ICAMs also play a role in disease, including leukocyte adhesion deficiency, dry eye disease, cardiovascular disease, intestinal inflammation, pulmonary fibrosis, and autoimmunity. The study of ICAMs is important for understanding the pathogenesis of these diseases and for developing therapeutic strategies.