Cadmium (Cd<sup>2+</sup>) is a non-essential heavy metal, which is taken up from the environment into the body through pulmonary and enteral pathways. The S1 segment of the kidney proximal tubule (PT) is a major target of chronic Cd<sup>2+</sup> toxicity. Renal dysfunction develops in up to 7% of the general population and in its most severe form displays major features of Fanconi syndrome, such as a defective protein, amino acid, glucose, bicarbonate and phosphate reabsorption. The major pathway for Cd<sup>2+</sup> uptake by PT cells (PTCs) in vivo is apical endocytosis of Cd<sup>2+</sup> complexed to the high-affinity metal-binding protein metallothionein (MT), which may be receptor-mediated. MT is subsequently degraded in endo-lysosomes, and Cd<sup>2+</sup> is liberated for translocation into the cytosolic compartment, possibly using transporters for Fe<sup>2+</sup>, Zn<sup>2+</sup> or Cu<sup>2+</sup>, such as the divalent metal transporter DMT1. Free Cd<sup>2+</sup> ions in the extracellular space are translocated across apical and/or basolateral PTC membranes into the cytosol via transporters, whose identity remains unknown. Cytosolic Cd<sup>2+</sup> generates reactive oxygen species (ROS), which deplete endogenous radical scavengers. ROS also damage a variety of transport proteins, including the Na<sup>+</sup>/K<sup>+</sup>-ATPase, which are subsequently degraded by the proteasome and endo-lysosomal proteases. Cd<sup>2+</sup> causes mitochondrial swelling and release of cytochrome c. If these ROS-mediated stress events are not balanced by repair processes, affected cells undergo apoptosis. But Cd<sup>2+</sup> also induces the upregulation of cytoprotective stress and metal-scavenging proteins, such as MT. In addition, Cd<sup>2+</sup> upregulates the detoxifying pump multidrug resistance P-glycoprotein, which appears to protect PTCs against Cd<sup>2+</sup>-induced apoptosis. Thus, Cd<sup>2+</sup> interferes with various cellular events ranging from mechanisms of induction of programmed cell death to activation of cell survival genes. A better understanding of the cellular mechanisms involved in Cd<sup>2+</sup> nephrotoxicity should provide insights into other heavy metal (e.g. Pb<sup>2+</sup>, Hg<sup>2+</sup>) nephropathies and various forms of acquired Fanconi syndrome.