The role of factor XIII subunit A (FXIII‐A) is not restricted to hemostasis. FXIII‐A is also present intracellularly in several human cells and serves as a diagnostic marker in a wide range of dermatological diseases from inflammatory conditions to malignancies. In this review, we provide a guide on the still controversial interpretation of dermal cell types expressing FXIII‐A and assess the previously described mechanisms behind their accumulation under physiological and pathological conditions of the human skin. We summarize the intracellular functions of FXIII‐A as well as its possible sources in the extracellular space of the dermis with a focus on its relevance to skin homeostasis and disease pathogenesis. Finally, the potential role of FXIII‐A in wound healing, as a field with long‐term therapeutic implications, is also discussed.