Cadmium (Cd) is an industrial and environmental pollutant that affects adversely a number of organs in humans and other mammals, including the kidneys, liver, lungs, pancreas, testis, and placenta. The liver and kidneys, which are the primary organs involved in the elimination of systemic Cd, are especially sensitive to the toxic effects of Cd. Because Cd ions possess a high affinity for sulfhydryl groups and thiolate anions, the cellular and molecular mechanisms involved in the handling and toxicity of Cd in target organs can be defined largely by the molecular interactions that occur between Cd ions and various sulfhydryl-containing molecules that are present in both the intracellular and extracellular compartments. A great deal of scientific data have been collected over the years to better define the toxic effects of Cd in the primary target organs. Notwithstanding all of the new developments made and information gathered, it is surprising that very little is known about the cellular and molecular mechanisms involved in the uptake, retention, and elimination of Cd in target epithelial cells. Therefore, the primary purpose of this review is to summarize and put into perspective some of the more salient current findings, assertions, and hypotheses pertaining to the transport and handling of Cd in the epithelial cells of target organs. Particular attention has been placed on the molecular mechanisms involved in the absorption, retention, and secretion of Cd in small intestinal enterocytes, hepatocytes, and tubular epithelial cells lining both proximal and distal portions of the nephron. The purpose of this review is not only to provide a summary of published findings but also to provide speculations and testable hypotheses based on contemporary findings made in other areas of research, with the hope that they may promote and serve as the impetus for future investigations designed to define more precisely the cellular mechanisms involved in the transport and handling of Cd within the body.