Cell adhesion molecules are cell surface proteins that play critical roles in cell recognition and cell adhesion. These adhesion molecules, which include the cadherins, integrins, occludins, and a variety of immunoglobulin-like molecules, are essential for a wide variety of physiologic processes such as epithelial barrier function, tissue development, learning and memory, and immune responses. In light of the evidence that toxic metals can affect many of these processes, investigators have begun to examine the possibility that cell adhesion molecules may be targets for metal toxicity. This review summarizes the results of recent studies showing that certain cell adhesion molecules, particularly the cadherins family of Ca(2+)-dependent cell adhesion molecules and the immunoglobulin family of Ca(2+)-independent cell adhesion molecules, may be important early targets on which toxic metals such as a Cd, Hg, and Pb act to produce their toxic effects. These metals, and in some cases their organic compounds, can target cell adhesion molecules at multiple levels, including protein-protein interactions, post-translational modification, and transcriptional regulation. Moreover, by interfering with the normal function of the cadherin family of cell adhesion molecules, some of these metals may activate the beta-catenin nuclear signaling pathway. These studies have provided important new insights into the molecular mechanisms of metal toxicity and have opened several exciting avenues of research.