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N-acetyl galactosamine (GalNAc)-conjugated siRNAs have achieved remarkable clinical success with six FDA-approved therapeutics targeting liver diseases. Following subcutaneous administration, GalNAc\u2013siRNAs rapidly accumulate in hepatocytes via asialoglycoprotein receptor (ASGPR)-mediated endocytosis and are sequestered within endolysosomal compartments, creating an intracellular depot that sustains therapeutic effects for weeks to months. While RNAi-mediated degradation and nuclease metabolism contribute to siRNA clearance, the detection of full-length, active siRNA in circulation long after dosing suggests alternative clearance mechanisms exist. This review examines the pharmacokinetic properties and intracellular trafficking of GalNAc\u2013siRNA, with particular focus on underexplored clearance pathways from hepatocytes. 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