A subset of celiac disease (CD) patients is, or becomes, refractory to a gluten-free diet with persistent malabsorption and intestinal villous atrophy (VA). The most common cause of this condition is inadvertent gluten exposure but concomitant diseases and alternative diagnoses resulting in VA should also be considered and excluded. Differential diagnosis between inadvertent gluten exposure, slow responsive disease, non-responsive CD, and refractory celiac disease (RCD) is frequently difficult. This review will summarize the current knowledge on epidemiology, pathogenesis, and the diagnostic armamentarium of RCD, as well as a review of past and current therapies.