While it has been well demonstrated that quantum dots (QDs) play an important role in biological labeling both in vitro and in vivo, there is no report describing the cellular nanostructure basis of receptor-mediated endocytosis. Here, nanostructure evolution responses to the endocytosis of transferrin (Tf)-conjugated QDs were characterized by atomic force microscopy (AFM). AFM-based nanostructure analysis demonstrated that the Tf-conjugated QDs were specifically and tightly bound to the cell receptors and the nanostructure evolution is highly correlated with the cell membrane receptor-mediated transduction. Consistently, confocal microscopic and flow cytometry results have demonstrated the specificity and dynamic property of Tf-QD binding and internalization. We found that the internalization of Tf-QD is linearly related to time. Moreover, while the nanoparticles on the cell membrane increased, the endocytosis was still very active, suggesting that QD nanoparticles did not interfere sterically with the binding and function of receptors. Therefore, ligand-conjugated QDs are potentially useful in biological labeling of cells at a nanometer scale.