Both skin and oral mucosa are characterized by the presence of keratinized epithelium in direct apposition to an underlying collagen-dense connective tissue. Despite significant overlap in structure and physiological function, skin and the oral mucosa exhibit significantly different healing profiles in response to injury. The oral mucosa has a propensity for rapid restoration of barrier function with minimal underlying fibrosis, but in contrast, skin is associated with slower healing and scar formation. Modulators of cell function, matricellular proteins have been shown to play significant roles in cutaneous healing, but their role in restoration of the oral mucosa is poorly defined. As will be discussed in this review, over the last 12 years our research group has been actively investigating the role of the profibrotic matricellular protein periostin in tissue homeostasis and fibrosis, as well as healing, in both skin and gingiva. In the skin, periostin is highly expressed in fibrotic scars and is upregulated during cutaneous wound repair, where it facilitates myofibroblast differentiation. In contrast, in gingival healing, periostin regulates extracellular matrix synthesis but does not appear to be associated with the transition of mesenchymal cells to a contractile phenotype. The significance of these findings will be discussed, with a focus on periostin as a potential therapeutic to augment healing of soft tissues or suppress fibrosis.