Junctional adhesion molecule‐A (JAM‐A) is a critical signaling component of the apical junctional complex, a structure composed of several transmembrane and scaffold molecules that controls the passage of nutrients and solutes across epithelial surfaces. Observations from JAM‐A–deficient epithelial cells and JAM‐A knockout animals indicate that JAM‐A is an important regulator of epithelial paracellular permeability; however, the mechanism(s) linking JAM‐A to barrier function are not understood. This review highlights recent findings relevant to JAM‐A–mediated regulation of epithelial permeability, focusing on the role of upstream and downstream signaling candidates. We draw on what is known about proteins reported to associate with JAM‐A in other pathways and on known modulators of barrier function to propose candidate effectors that may mediate JAM‐A regulation of epithelial paracellular permeability. Further investigation of pathways highlighted in this review may provide ideas for novel therapeutics that target debilitating conditions associated with barrier dysfunction, such as inflammatory bowel disease.