Besides the traditional topical treatment of mild and moderate forms of atopic dermatitis (AD), which includes the daily use of emollients and the intermittent use of topical corticosteroids (TCSs) as anti-inflammatory drugs, a new group of drugs has recently been introduced to control the inflammatory phase of the disease: topical calcineurin inhibitors (TCIs). Although the efficacy of TCSs is evident, prolonged unrestricted use is limited by local and systemic side effects. The major risk in children is the hypothalamic-pituitary-adrenal gland suppression, due to the higher percutaneous absorption of the TCSs. TCIs selectively block the activity of calcineurin, a serin/threonine protein phosphatase regulated by cellular calcium first detected in skeletal muscle and brain. Within the past few years, calcineurin has been implicated in a wide range of biological responses including lymphocyte activation, neuronal and muscle development, and morphogenesis of heart valves. TCIs disrupt the intracellular signalling towards NF-AT by forming a complex with macrophilin-12. This complex inhibits the activity of calcineurin, thereby preventing the dephosphorylation of NF-AT and so interfering with the transcription of several genes. The nuclear component of NF-AT, binding to its nuclear counterpart, is essential for the transcription of various genes, including interleukin (IL)-2 and other proinflammatory cytokines. Recent findings about the therapeutic efficacy of TCIs have provided a possible alternative to TCSs in the treatments of mild to severe forms of AD.