Macrophages play a crucial role in the innate immune system. They are present in most tissues, where they contribute to maintain homeostasis. Kupffer cells have specialized immunometabolic functions that link immune regulation and metabolic homeostasis directly. This enables them to regulate hepatic metabolism by controlling lipid handling and inflammatory responses. Consequently, there is growing interest in developing strategies to selectively modulate the function, polarity, distribution, behavior, and phenotype of Kupffer cells depending on the pathophysiological context. Given their plasticity and contribution to metabolic dysfunction-associated steatotic liver disease (MASLD), it is of increasing interest to find strategies that can selectively modulate Kupffer cell's plasticity to control their distribution and phenotype depending on the pathophysiological context. This would modify their interaction with other cells in the liver niche, particularly hepatocytes, in the context of both atherosclerosis and MASLD. Future perspectives should focus on understanding how changes in the uptake capacity of Kupffer cells occur under conditions of lipid overload, and on exploring paracrine signals within the liver that can modulate their activation using advanced techniques such as high resolution spatial liver profiling.