The liver is key to glucose homeostasis. Any disruption of its metabolism, structural integrity, or intracellular dynamics may alter the liver's ability to maintain normal glucose homeostasis. When such disruption affects hepatic glucose output, hypoglycemia may eventuate. Multiple drugs including alcohol may alter the intrahepatic pathways that are vital for normal glucose production by the liver. Spontaneous hypoglycemia always warrants an evaluation of hepatic function and a careful scrutiny of medications that affect hepatic structural or biochemical integrity.