Summary Background  The safety of topical therapies for atopic dermatitis (AD), a common and morbid disease, has recently been the focus of increased scrutiny, adding confusion as how best to manage these patients. Objectives  The objective of these systematic reviews was to determine the safety of topical therapies for AD. Methods  Databases searched included: OVID Medline, Medline In‐Process and Other Non‐Indexed Citations, Embase, and the Cochrane Central Register of Controlled Trials. In addition to the articles identified by this search, investigators were also referred to a list of links (most recently updated 25 September 2005) to recent Food and Drug Administration (FDA) studies, reports and meetings regarding the topical calcineurin inhibitors for further potential references. Only fully published papers available in English and data obtained from FDA sites were included. Furthermore, the criteria for inclusion and exclusion for each systematic review were further evaluated at a meeting of all of the content and evidence‐based medicine experts participating in this process and alteration of the inclusion criteria was done at that time when it was felt necessary to avoid inclusion of lower‐quality data in the review. Qualitative review of the ed data was performed and reviewed at a meeting of all of the content and evidence‐based medicine experts. Results  While systemic exposure to these topical agents does occur, physiological changes appear to be uncommon and systemic complications rare and have only been found with use of topical corticosteroids. Conclusions  Based on the data that are available the overall safety of AD therapies appears to be good with the only documented systemic side‐effects of therapy those occasionally seen with use of topical corticosteroids.