Cadmium (Cd)-based QDs are well studied owing to their excellent optical properties. The applications of Cd-based QDs in biomedical filed, however, is hindered by its inherent toxicity. In this study, to overcome the inherent toxicity of heavy metals, CdTe QDs were encapsulated with different shells (NAC, MPA and GSH) to reduce the leakage of Cd from the core. We studied the cytotoxicity of the three kinds of CdTe QDs on S. cerevisiae by spectroscopic, electrochemical, microscopic methods and microcalorimetric technique. Results showed that toxicity of CdTe QDs increased with the augment of QD concentration. According to the values of IC50 ((GSH-CdTe QDs (15.3 nmol/L) < MPA-CdTe QDs (56.2 nmol/L) < NAC-CdTe QDs (89.8 nmol/L)), the most toxic one is GSH-CdTe QDs, followed by MPA-CdTe QDs, then NAC-CdTe QDs. The coatings have contribution to their toxicity. The three kinds of QDs with the similar shape (sphere) can enter the cell by the clathrin-mediated endocytosis and lead to the different impairments. The mechanism of cytotoxicity is due to the release of Cd2+ leading elevation of intracellular reactive oxygen species (ROS), which damage mitochondria. The clathrin-mediated endocytosis is a significant factor in determining the toxicity of CdTe QDs.