**Abstract**

For several years,researchers have targeted receptors overexpressed on cancer cells to improve the selectivity of toxic anticancer agents. In addition to conjugating the toxin to an antibody for such a receptor, the natural ligand for the overexpressed receptor has also been used as a protein‐based drug delivery vehicle. The therapeutic efficacy of such ligand‐drug molecular conjugates, however, may be limited, since they naturally follow the intracellular trafficking pathways of the endogenous ligands, which have certainly not been optimized by nature for drug delivery efficacy. Accordingly, novel design criteria may be identified for these ligands through an understanding of theirintracellulartrafficking pathways. This shortreview briefly describes the transferrin ligand/transferrin receptor system, where intracellular trafficking considerations have led to improvements in the therapeutic efficacy of transferrin‐toxin molecular conjugates.
