For adults with atopic dermatitis (AD) refractory to topical treatment, the choices of second-line therapy are limited. Furthermore, there are concerns about the long-term safety of treatments such as cyclosporin. Limited open studies suggest that azathioprine may be effective, although controlled trial data is lacking. Nevertheless, many UK dermatologists use azathioprine to treat patients with severe AD, despite the potential risk of serious toxicity. Azathioprine myelotoxicity and drug efficacy are now known to be related to the activity of a key enzyme in azathioprine metabolism, thiopurinemethyltransferase (TPMT). Recently, the facility for TPMT measurement has become more widely available, providing the possibility to optimize the therapeutic effect of azathioprine, yet minimise the risk of toxicity. We review the evidence concerning the use of azathioprine for AD, and have identified 128 cases in eight open studies, including our own prospective trial. Improvement in the majority was noted in seven studies, although objective measures of disease activity were used in only one trial. Measurements of TPMT activity were performed in the two most recent studies only. These data underscore the requirement for a prospective randomised controlled trial, and highlight the need to further investigate the role of TPMT measurement in azathioprine usage.