Clathrin heavy chain (CHC) is a critical component of the clathrin protein complex, which is involved in intracellular trafficking, particularly in clathrin-mediated endocytosis (CME). The major function of neuronal clathrin is to recycle synaptic vesicle proteins following exocytosis. Clathrin heavy chain is probably the limiting component in triskelion biosynthesis, and an increase in the amount of clathrin heavy chain may reflect control of triskelion synthesis. Clathrin-mediated pathways are linked to disease and tissue differentiation. The balance of cargo sequestration into CCVs can affect cell fate, linking clathrin-mediated pathways to disease.