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.