The fifth scientific workshop of the European Crohn's and Colitis Organization (ECCO) focused on the relevance of fistulas to the disease course of patients with Crohn's disease (CD). The objectives were: a better understanding of the pathophysiological mechanisms underlying the formation of CD fistulas; identification of future topics in fistula research that could provide insights into pathogenesis; the development of novel therapeutic approaches; and a review of current therapeutic strategies (with clarification of existing approaches to prevention, diagnosis and treatment).The results of the workshop are presented in two separate manuscripts. This manuscript describes current state-of-the-art knowledge about fistula pathogenesis, including the roles of epithelial-to-mesenchymal-transition and cytokine matrix remodelling enzymes, and it highlights the common association between fistulas and stenosis in CD. Further, the review considers the possible roles that genetic predisposition and intestinal microbiota play in fistula development. Finally, it proposes future directions and needs for fistula research that might substantially increase our understanding of this complex condition and help unravel novel therapeutic strategies and specific targets for treatment. Overall, it aims to highlight unanswered questions in fistula research and to provide a framework for future research work.