The activated leukocyte cell adhesion molecule [ALCAM/CD166/melanoma metastasis clone D (MEMD)] is an immunoglobulin superfamily cell adhesion molecule. It is expressed developmentally in cells of all 3 embryonic lineages. The ALCAM expression is limited to subsets of cells in most adult tissues. ALCAM is localized at intercellular junctions in epithelium presumably as part of the adhesive complex that maintains tissue architecture. Over the past decade, alterations in expression of ALCAM have been reported in several human tumors (melanoma, prostate cancer, breast cancer, colorectal carcinoma, bladder cancer, and esophageal squamous cell carcinoma). This review summarizes the current knowledge of the role of ALCAM in malignancies.