The endoplasmic reticulum (ER) is a complex network of membrane-bound cavities that permeates the entire cytoplasm from the cell membrane to the nucleus. Its discovery began in 1945 when Porter, Claude, and Fullam observed a "lace-like" reticulum in cultured cells using electron microscopy. The ER was characterized by its reticular disposition and vesicular components, which were later confirmed in sectioned cells. The shift from spread to sectioned cytological specimens revealed significant geometrical challenges, particularly the difficulty in maintaining the continuity of the ER in sections due to the smaller thickness of sections compared to the reticulum's mesh size. The ER varies in volume, organization, and structure across different cell types, reflecting its involvement in cell differentiation. For example, seminal epithelia exhibit a randomly disposed, smooth-surfaced ER, while liver cells show a tightly packed, randomly disposed network of cisternae. The ER is also found in various cell types, including macrophages, liver cells, and pancreatic acinar cells, where it plays roles in intracellular transport, metabolism, and cell signaling. Recent studies have highlighted the ER's connections with other cellular structures, such as the Golgi apparatus and the cell membrane, suggesting its involvement in matter exchange and intracellular circulation. The ER's continuous membrane separates two main phases in the cytoplasm, providing a large surface area for metabolic reactions and potentially functioning as an intracellular conductor or segregation apparatus. Despite these findings, the biochemistry and physiology of the ER remain largely unknown, and its role in cell physiology is still speculative. The ER's multifaceted nature challenges traditional concepts in cell biology, particularly regarding the permeability of the cell membrane.The endoplasmic reticulum (ER) is a complex network of membrane-bound cavities that permeates the entire cytoplasm from the cell membrane to the nucleus. Its discovery began in 1945 when Porter, Claude, and Fullam observed a "lace-like" reticulum in cultured cells using electron microscopy. The ER was characterized by its reticular disposition and vesicular components, which were later confirmed in sectioned cells. The shift from spread to sectioned cytological specimens revealed significant geometrical challenges, particularly the difficulty in maintaining the continuity of the ER in sections due to the smaller thickness of sections compared to the reticulum's mesh size. The ER varies in volume, organization, and structure across different cell types, reflecting its involvement in cell differentiation. For example, seminal epithelia exhibit a randomly disposed, smooth-surfaced ER, while liver cells show a tightly packed, randomly disposed network of cisternae. The ER is also found in various cell types, including macrophages, liver cells, and pancreatic acinar cells, where it plays roles in intracellular transport, metabolism, and cell signaling. Recent studies have highlighted the ER's connections with other cellular structures, such as the Golgi apparatus and the cell membrane, suggesting its involvement in matter exchange and intracellular circulation. The ER's continuous membrane separates two main phases in the cytoplasm, providing a large surface area for metabolic reactions and potentially functioning as an intracellular conductor or segregation apparatus. Despite these findings, the biochemistry and physiology of the ER remain largely unknown, and its role in cell physiology is still speculative. The ER's multifaceted nature challenges traditional concepts in cell biology, particularly regarding the permeability of the cell membrane.