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Quantum dots (QDs) are colloidal nanocrystalline semiconductors with unique optical and electrical properties (Bruchez et al. 1998). As a new class of inorganic fluorophore, which has the advantages of broad absorption spectra, narrow emission spectra, stable photostability, and long fluorescent lifetime, QDs are gaining widespread recognition and are rapidly applied to fluorescent labeling of cellular proteins (Kaul et al. 2003; Mansson et al. 2004; Sukhanova et al. 2004), cell tracking (Dubertret et al. 2002; Jaiswal et al. 2003), and even imaging in vivo (Akerman et al. 2002; Chen et al. 2004; Gao et al. 2004; Lim et al. 2003; Morgan et al. 2005). Although some reports have evaluated the cytotoxicity of various QDs in different cell lines under different circumstances (Chan et al. 2006; Kirchner et al. 2005; Lovric et al. 2005; Zhang et al. 2006), little is known about QD toxicity both in vivo and in vitro. Santra et al. successfully labeled brain tissue with TAT-conjugated CdSratioMn/ZnS QDs that were intraarterially delivered to the rat brain (Santra et al. 2005), but this method of brain tissue labeling raised subsequent worries about QD toxicity on the toxin-susceptible brain. In fact, many QDs may seem harmless, but they can be destabilized because of their sequestration in tissues and long-term exposure to the bioenvironment. Cell structures and functions can be impaired when cells are exposed to unstable, poorly capped, or coated QDs (Choi et al. 2007, 2008; Hardman 2006; Lovric et al. 2005). In other words, even if the QDs are well modified, the potential risks are still present in subsequent biologic and clinical applications of QDs. In the central nervous system (CNS), voltage-gated sodium channels (VGSCs) are responsible for both initiation and propagation of action potentials of the neurons. Therefore, potential modulation of the functional properties of VGSCs by QDs would be expected to alter the activity and functions of CNS neurons. Meanwhile, there is hardly a biological reaction in the CNS that is not regulated, directly or indirectly, by calcium ions. Transient rises of calcium ions in the cytoplasmic levels are believed to serve as second messenger signals that control numerous neuronal functions, whereas sustained elevation of cytoplasmic calcium levels is obviously deleterious to various neuronal functions. Of even greater concern is that the sustained increase of intra-cellular calcium may result in cell apoptosis/ death (Fox et al. 1999; McConkey and Orrenius 1996; Nicotera et al. 1994). Some reports have shown that QDs could impair cell functions and even induce cell apoptosis or death in certain cell lines (Chan et al. 2006; Choi et al. 2007, 2008; Medintz et al. 2005), but these studies mostly focused on the free Cd2+ (QD core degradation), free radical formation, and interaction of QDs with intracellular components, and little attention has been paid to the potential toxicity exerted by QDs through intracellular calcium steady-state and functional properties of neuronal ion channels. Using confocal laser scanning and standard whole-cell patch clamp techniques, the present study explored the potential for the neurotoxicity of unmodified cadmium selenium (CdSe) QDs in a rat primary hippocampal culture model, focusing on cytoplasmic calcium levels and VGSC functions.