The advent of tacrolimus at the end of the preceding century in the armamentarium of atopic dermatitis management was hailed as a breakthrough advance. It was, therefore, thought worthwhile to precisely review its origin and mechanism of action. Its topical application in the form of 0.03% to 0.1% ointments is rapidly effective and safe in pediatric and adult patients. Its use in atopic dermatitis ever since has been approved in Japan, the United States, Europe, and the Indian subcontinent. Thus, its local immunosuppressive action was fairly intriguing. Accordingly, its indications/uses were extended to cover several inflammatory dermatoses. Vitiligo, psoriasis, alopecia areata, contact hypersensitivity, lichen planus, pyoderma gangrenosum, ichthyosis linearis circumflexa, and skin grafting/transplant are a few unapproved indications and uses, in addition to miscellaneous dermatoses. At present, its therapeutic efficacy other then atopic dermatitis is confined to case studies, and large studies are warranted. At this point in time, therefore, it is conceivable that tacrolimus use should be carefully evaluated and used only when the conventional treatment has failed to yield favorable results. It deserves sizable caution for use in various dermatologic conditions pending its long-term safety and efficacy data in large patient populations.