The development of multicellular organisms depends on cell adhesion molecules (CAMs) that connect cells to build tissues. The immunoglobulin superfamily (IgSF) constitutes one of the largest families of CAMs. Members of this family regulate such diverse processes like synapse formation, spermatogenesis, leukocyte-endothelial interactions, or epithelial cell-cell adhesion. Through their extracellular domains, they undergo homophilic and heterophilic interactions in cis and trans. Their cytoplasmic domains frequently bind scaffolding proteins to assemble signaling complexes. Transmembrane and immunoglobulin domain-containing protein 1 (TMIGD1) is a IgSF member with two Ig-like domains and a short cytoplasmic tail that contains a PDZ domain-binding motif. Recent observations indicate that TMIGD1 has pleiotropic functions in epithelial cells and has a critical role in suppressing malignant cell behavior. Here, we review the molecular characteristics of TMIGD1, its interaction with cytoplasmic scaffolding proteins, the regulation of its expression, and its downregulation in colorectal and renal cancers.