Recent studies indicate that plakoglobin may have a similar function to that of β‐catenin within the Wnt signaling pathway. β‐catenin is known to be an oncogene in many forms of human cancer, following acquisition of stabilizing mutations in amino terminal sequences. Kolligs(1) and coworkers show, however, that unlike β‐catenin, plakoglobin induces neoplastic transformation of rat epithelial cells in the absence of such stabilizing mutations. Cellular transformation by plakoglobin also appears to be distinct from that of β‐catenin in that it requires activation of the proto‐oncogene c‐myc. Surprisingly, c‐myc is activated more efficiently by plakoglobin than β‐catenin, despite its previous identification as a target of Tcf/β‐catenin.(2) In contrast, a synthetic Tcf reporter gene is activated to a much greater extent by β‐catenin than plakoglobin. Plakoglobin and β‐catenin may therefore have different roles in Wnt signaling and cancer, which reflect their differential effects on target gene activity. BioEssays 22:961–965, 2000. © 2000 John Wiley & Sons, Inc.