p0071, a member of the armadillo protein family, is most closely related to p120(ctn) and the plakophilins 1-3. Whereas plakophilins are desmosomal plaque proteins, p120(ctn) localizes to adherens junctions and interacts with classical cadherins. In contrast, p0071 has been described as a protein with dual localization in adherens junctions and desmosomes depending on the cell type examined. Here we have analyzed the localization of p0071 and its domains in detail. Although by sequence analysis, p0071 is more closely related to the adherens junction proteins p120(ctn), ARVCF and delta-catenin, endogenous p0071 associated preferentially with desmosomes in MCF-7 epithelial cells. Overexpressed p0071 localized along cell borders and overlapped only partially with desmosomal markers but colocalized with non-desmosomal cadherins and recruited cadherins to the membrane. The head domain of p0071 was sufficient for desmosomal targeting, whereas the arm repeat domain associated with adherens junctions and enhanced membrane association of classical cadherins. The tail domain localized preferentially to the nucleus and associated with desmosomes. To examine the mechanism underlying this dual localization more closely we determined binding partners of p0071 by using yeast-two-hybrid and mom-targeting assays. These approaches show that the head domain interacted with desmosomal proteins desmocollin 3a and desmoplakin, whereas the armadillo repeat domain binds to non-desmosomal cadherins. Head and armadillo repeat domains both interacted with plakoglobin by binding to different sites. Our data suggest that, in addition to plakoglobin, p0071 is the second armadillo protein present in both types of adhesive junctions and may play a role in regulating crosstalk between adherens junctions and desmosomes.