Antimalarials, such as chloroquine and hydroxychloroquine, have been used to treat cutaneous and systemic lupus erythematosus for decades with excellent therapeutic efficacy. Smoking seems to inhibit the therapeutic efficacy of antimalarials when treating cutaneous lupus erythematosus (CLE), but the reason behind this observation is unclear. In addition, antimalarials have been associated with several potentially serious adverse effects, including irreversible loss of vision. The aim of this literature review is to discuss the evidence for how cigarette smoking interferes with antimalarial efficacy in the treatment of CLE. Evidence-based data with long-term follow-up will allow determination of the aetiology for diminished antimalarial response, and enable selection of the best treatment to maximize long-term remission in CLE.