Cutaneous lupus erythematosus (CLE) is one of the most common dermatological autoimmune disorders worldwide. Recently, several studies provided evidence for a pathogenic role of type I interferons (IFNs) in this disease. Plasmacytoid dendritic cells are major type I IFN producers in CLE skin lesions. Type I IFNs are able to induce the expression of several proinflammatory chemokines, including CXCL9 and 10, and enhance the cytotoxic capacity of infiltrating cells. Additionally, adhesion molecules and chemokine receptors, such as intercellular adhesion molecule-1, cutaneous lymphocyte antigen, E-selectin, CCR4 and CXCR3, are involved in the recruitment of potentially autoreactive lymphocytes into the skin. Here, we review the role of type I IFNs, adhesion molecules and chemokine receptors in CLE and discuss options for novel therapeutic approaches.