Chronic graft-versus-host disease (cGVHD), a multiorgan disorder, is the leading cause of late nonrelapse mortality (NRM) after hematopoietic stem cell transplantation (HSCT). Despite many years of experience with this disease we are still faced with numerous challenges including (among others); lack of reliable preclinical models, poor knowledge of human pathophysiology, validated diagnostic and severity criteria, and unpredictable clinical response to first line treatment. We will review recent advances on the 3 last mentioned unresolved areas.