Pimecrolimus and tacrolimus represent the first members of a new class of medications, calcineurin inhibitors. These topical macrolide immunomodulators have been successfully introduced in the treatment of atopic dermatitis. They inhibit T cell proliferation, mast cell degranulation, production and release of IL-2, IL-4, IF-γ and TNF-α. They do not effect endothelial cells and fibroblasts, so they do not induce skin atrophy. In several studies, it has been shown that topical pimecrolimus and tacrolimus are effective, well tolerated and safe in both adults and children with atopic dermatitis. Pimecrolimus permeates less through the skin than tacrolimus and much less than corticosteroids. It has a lower potential for transcutaneous absorption resulting in a lower risk of systemic effects. In addition, they have been used in other inflammatory skin diseases including psoriasis, lichen planus, seborrheic dermatitis, allergic contact dermatitis, vitiligo, pyoderma gangrenosum, alopecia areata, graft versus host disease, akne rosacea, etc. In this review article mechanism of action, efficacy, safety of pimecrolimus and tacrolimus, and future directions of these immunomodulators were discussed.