Recent developments in the structure of erythrocyte band 3 and its role in hereditary spherocytosis and distal renal tubular acidosis are described. The crystal structure of the N-terminal cytoplasmic domain provides a basis for understanding the organization of ankyrin and other peripheral membrane proteins around band 3. Band 3 also binds integral membrane proteins, including the Rh protein complex and CD47. Band 4.2 is important in these associations, which link the Rh complex to the skeleton. It is suggested that band 3 forms the scaffold for a protein assembly that could transduce signals from the cell exterior and modulate the transport and mechanical properties of the erythrocyte. The involvement of band 3 in distal renal tubular acidosis is reviewed. The article discusses a likely mechanism for dominant distal renal tubular acidosis in which associations between the normal and mutant protein alter the plasma membrane targeting of the normal protein in the kidney.