Janus kinase inhibitors (JAKi) are small molecules which prevent the phosphorylation of JAKs, thereby blocking the intracellular phosphorylation cascade required for the transcription of several cytokines. In addition to approved indications that have been extensively studied, including atopic dermatitis, alopecia areata, vitiligo and psoriasis, JAKi are also proposed off-label, included topically, in several dermatological conditions where standard treatments are often disappointing, such as hidradenitis suppurativa (HS), extensive morphea, cutaneous sarcoidosis and lichen planus. On the other hand, the wide mechanism of action on cytokine blockade implies a safety profile that requires a case-by-case assessment of the risk/benefit ratio before their introduction.