Calcineurin inhibitors are immunomodulator macrolides that block T cell activation in the skin. These molecules bind to macrophilin 12 to form a complex capable of blocking calcineurin, a protein that dephosphorylates, and thereby activates, the cytoplasmic subunit of nuclear factor of activated T cells (NF-AT). Thus, in the presence of calcineurin inhibitors, NF-AT cannot enter the nucleus and interact with the promoter regions of many cytokine genes. In addition to T cells, calcineurin inhibitors have also been shown to inhibit the activation of a number of other cell types in the skin immune system, including eosinophils, basophils, and Langerhans cells. These drugs are highly effective in treating atopic dermatitis, even in monotherapy, and they result in rapid, progressive, and sustained improvement. Additionally, calcineurin inhibitors are well tolerated for long-term treatment, and there are virtually no contraindications when using these medications on the face, eyelids, flexural skin, or mucous membranes. Although calcineurin inhibitors are immunomodulators, no significantly increased incidence of infections can be detected during therapy. Cutaneous lupus erythematosus is a chronic, autoimmune, inflammatory skin condition with a wide spectrum of skin manifestations, which presents a therapeutic challenge for dermatologists. In this review, the current treatment options for the different clinical subtypes of this disease are discussed. Therapy with topical calcineurin inhibitors is emphasized, and advantages and drawbacks, effects and side effects, treatment protocols, dosage, and expected outcome are described in detail.