The Fras1 and Frem extracellular matrix proteins play critical roles in epithelial-mesenchymal interaction during embryonic development. Loss of function in humans results in a recessive embryonic blistering disorder called Fraser syndrome. Inactivation of these proteins, or the proteins with which they interact (e.g., Grip1) has also been shown to underlie members of the 'bleb' family of classic mouse mutants which provide a valuable model of Fraser syndrome. Recent studies supporting direct interactions between the Fras1 and Frem proteins, combined with more rigorous elucidation of their developmental regulation, have shed new light on their activity. We summarize the findings to date, bringing new insight into their role in the regulation of epidermal-basement membrane adhesion and organogenesis during development.