Over the last few years, understanding of the pathophysiology of toxic epidermal necrolysis (TEN), or Lyell's disease, has substantially increased. However, differentiation of severe bullous skin disease remains a challenge for the clinician, and one that is often complicated by late patient referral. We performed a retrospective analysis of all patients with severe bullous skin disease, admitted between 1997 and 2002 to the Burn Centre, which is an integrated part of the Division for Plastic, Hand- and Reconstructive Surgery at the University Hospital of Zurich, Switzerland. We present an overview of our strategies and of the diagnostic and therapeutic difficulties encountered. The final diagnoses of the 18 patients referred to the unit were as follows: eight cases of TEN, one case of staphylococcal scalded-skin syndrome (SSSS), two cases of generalised drug eruption, one case of acute generalised exanthematic pustulosis and one case of febrile ulceronecrotic pityriasis lichenoides et varioliformis acuta (PLEVA). In two cases, the diagnosis remained unclear. In three cases, paraneoplastic origins were suspected but not demonstrated. The overall mortality rate was 33% (six of 18 patients). Remarkably, all patients with histologically confirmed TEN survived. Six of these patients were successfully treated with intravenous immunoglobulins (IVIG). The most common single causative drug inducing TEN (four cases out of eight) was Phenytoin. Establishing an accurate diagnosis-based on a skin biopsy, harvested at an early stage-is more important than ever, because more specific and effective therapeutic modalities are available. As these potentially life-threatening bullous skin disorders are rare, we recommend, that care be provided by an experienced interdisciplinary team, comprising a dermatologist, or dermatopathologist, an intensive care specialist and a plastic surgeon.