Throughout history, the liver has captivated human interest; spanning from the ancient ritual of hepatoscopy, where the livers of sacrificed animals were scrutinized to foretell the future, to the medical doctrine of hepatocentrism, which positioned the liver at the core of the human body [1,2]. In 1666, Marcello Malpighi's pioneering work in microscopic anatomy provided the first insights into the organization of liver parenchyma [3]. Although he speculated about the functional relationship between liver cells and the neighboring vascular structures, experimental tools were lacking to test his hypothesis.

Advancements in electron microscopy two centuries later revealed diverse hepatocyte subcellular organization leading to the concept of liver zonation—the spatial division of liver functions [4, 5, 6]. Although compartmentalization through physical separation from the environment, via a membrane, enables the efficient and coordinated execution of diverse biochemical processes, non-canonical forms of compartmentalization, such as liver zonation, have not been as extensively studied mainly due to technological shortcomings.

Recent developments, especially in single-cell technologies and tissue imaging, now provide an unprecedented opportunity to investigate liver zonation, regulation, and interactions between various cells in the physiological niche. This review focuses on recent in vivo discoveries in hepatic cell biology, the principles governing metabolic compartments, and outstanding questions. The following review articles on liver zonation are recommended for further reading [7, 8, 9].