Celiac disease is a gluten-sensitive enteropathy, which commits the patient to a life-long gluten-free diet. This is sufficient to treat the overwhelming majority of patients. However, a small group of these patients, mainly those diagnosed above 50 years of age, fails to improve histologically and clinically upon elimination of gluten from the diet. These patients are regarded as suffering from refractory celiac disease. In a subgroup of these patients a pre-malignant intraepithelial lymphocyte population can be detected in the small intestinal mucosa (type II). These patients are at a high risk of developing an enteropathy-associated T-cell lymphoma (50-60% within 4-6 years), which has a very poor prognosis and a 5-year survival of only 8%. The therapeutic challenge in these refractory celiac disease type II patients is targeting the aberrant intraepithelial lymphocytes to eventually prevent enteropathy-associated T-cell lymphoma development. Although management of these patients is difficult and therapeutic options are currently limited, novel treatment modalities are being explored.