Apolipoprotein E, first identified 26 years ago as a serum protein that mediates extracellular cholesterol transport, is now known to regulate multiple additional metabolic pathways. Several clinically important disorders of the vasculature and brain are differentially caused, or modified, by the three isoforms of this protein. Apolipoprotein E was previously believed to traffic exclusively through binding cell surface receptors, endocytosis, and hydrolysis. However, recent studies reveal a variety of additional physiologically important roles for apolipoprotein E that are mediated through interactions with different families of receptors, through binding other proteins, and through other intracellular trafficking pathways and second messengers. Much research is now directed toward identifying those pathways of apolipoprotein E metabolism that are differentially regulated by the various isoforms of apolipoprotein E, with the goal of identifying the particular molecular pathways that result in vascular and neurologic disorders.