Topical calcineurin inhibitors (pimecrolimus, Elidel, East Hanover, NJ; and tacrolimus, Protopic, Tokyo, Japan) have been approved for the use in atopic dermatitis since the year 2000. These compounds represent a relatively safe class of topical anti-inflammatory, nonsteroidal therapy. However, in January of 2006, the US Food and Drug Administration issued a black box warning on these compounds about possible concerns of increased long-term malignancy risk due to systemic immunosuppression. To date, studies from clinical trials, systemic absorption, and post-marketing surveillance show no evidence for this systemic immunosuppression or increased risk for any malignancy.